Process for C7 silylation of hydroxy substituted taxanes and intermediates thereof

ABSTRACT

Processes for the preparation of taxol and other taxanes through selective derivatization of the C(7) hydroxyl and C(10) hydroxyl groups of 10-DAB, particularly a novel process using a new strategy in which the C(10) hydroxyl group is protected or derivatized prior to the C(7) hydroxyl group; and the provision of C(7) and C(10) derivatized 10-DAB compounds.

This invention was made with Government support under NIH Grant #CA42031 awarded by the National Institutes of Health. The Government hascertain rights in the invention.

BACKGROUND OF THE INVENTION

The present invention is directed, in general, to a process for thepreparation of taxol and other taxanes, and in particular, to such aprocess in which the C(7) or C(10) hydroxyl group of a taxane isselectively derivatized.

10-DAB (1), which is extracted from the needles of taxus baccata L., theEnglish yew, has become a key starting material in the production oftaxol and Taxotere, both of which are potent anticancer agents.Conversion of 10-DAB to taxol, Taxotere® and other taxanes havingantitumor activity requires protection or derivatization of the C(7) andC(10) hydroxyl groups followed by-esterification of the C(13) hydroxylgroup to attach an appropriate side chain at that position.

Until now, strategies for the preparation of taxol and taxol analogswere based upon the observation of Senilh et al. (C. R. Acad. Sci.Paris, II, 1981, 293, 501) that the relative reactivity of the fourhydroxyl groups of 10-DAB toward acetic anhydride in pyridine isC(7)-OH>C(10)-OH>C(13)-OH>C(1)-OH. Denis, et. al. reported (J. Am. Chem.Soc., 1988, 110, 5917) selective silylation of the C(7) hydroxyl groupof 10-DAB with triethylsilyl chloride in pyridine to give7-triethylsilyl-10-deacetyl baccatin (III) (2) in 85% yield. Based uponthese reports, in those processes in which differentiation of the C(7)and C(10) hydroxyl groups is required (e.g., preparation of taxol from10-DAB), the C(7) hydroxyl group must be protected (or derivatized)before the C(10) hydroxyl group is protected or derivatized. Forexample, taxol may be prepared by treating 10-DAB with triethylsilylchloride to protect the C(7) hydroxyl group, acetylating the C(10)hydroxyl group, attaching the side chain by esterification of the C(13)hydroxyl group, and, finally, removal of protecting groups.

It is known that taxanes having various substituents bonded to eitherthe C(10) or the C(7) oxygens show anticancer activity. To provide formore efficient synthesis of these materials, it would be useful to havemethods which permit more efficient and more highly selective protectionor derivatization of the C(10) and the C(7) hydroxyl groups.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof highly efficient processes for the preparation of taxol and othertaxanes through selective derivatization of the C(7) group or the C(10)hydroxyl group of 10-DAB and other taxanes, particularly a process inwhich the C(10) hydroxyl group is protected or derivatized prior to theC(7) hydroxyl group; and the provision of C(7) or C(10) derivatizedtaxanes.

Briefly, therefore, the present invention is directed to a process forthe acylation of the C(10) hydroxy group of a taxane. The processcomprises forming a reaction mixture containing the taxane and anacylating agent which contains less than one equivalent of an amine basefor each equivalent of taxane, and allowing the taxane to react with theacylating agent to form a C(10) acylated taxane.

The present invention is further directed to a process for thesilylation of the C(10) hydroxy group of a taxane having a C(10) hydroxygroup. The process comprises treating the taxane with a silylamide or abissilylamide to form a C(10) silylated taxane.

The present invention is further directed to a process for convertingthe C(7) hydroxy group of a 10-acyloxy-7-hydroxytaxane to an acetal orketal. The process comprises treating the 10-acyloxy-7-hydroxytaxanewith a ketalizing agent in the presence of an acid catalyst to form aC(10) ketalized taxane.

The present invention is further directed to a taxane having thestructure:

wherein

M is a metal or comprises ammonium:

R₁ is hydrogen, hydroxy, protected hydroxy, or together with R₁₄ or R₂forms a carbonate;

R₂ is keto, —OT₂, acyloxy, or together with R₁ forms a carbonate;

R₄ is —OT₄ or acyloxy;

R₇ is —OSiR_(J)R_(K)R_(L);

R₉ is hydrogen, keto, —OT₉, or acyloxy;

R₁₀ is hydrogen, keto, —OT₁₀, or acyloxy;

R₁₃ is hydroxy, protected hydroxy, keto, or MO—;

R₁₄ is hydrogen, —OT₁₄, acyloxy, or together with R, forms a carbonate;

R_(J), R_(K), R_(L) are independently hydrocarbyl, substitutedhydrocarbyl, or heteroaryl, provided, however, if each of R_(J), R_(K)and R_(L) are alkyl, at least one of R_(J) R_(K) and R_(L) comprises acarbon skeleton having at least four carbon atoms; and

T₂/T₄, T₉, T₁₀, and T₁₄ are independently hydrogen or hydroxy protectinggroup.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Among other things, the present invention enables the selectivederivatization of the C(10) hydroxyl group of a taxane without firstprotecting the C(7) hydroxyl group. Stated another way, it has beendiscovered that the reactivities previously reported for the C(7) andC(10) hydroxyl groups can be reversed, that is, the reactivity of theC(10) hydroxyl group becomes greater than the reactivity of the C(7)hydroxyl group under certain conditions.

Although the present invention may be used to selectively derivatize ataxane having a hydroxy group at C(7) or C(10), it offers particularadvantages in the selective derivatization of taxanes having hydroxygroups at C(7) and C(10), i.e., 7,10-dihydroxy taxanes. In general,7,10-dihydroxytaxanes which may be selectively derivatized in accordancewith the present invention correspond to the following structure:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy, or together with R₁₄ or R₂forms a carbonate;

R₂ is keto, —OT₂, acyloxy, or together with R₁ forms a carbonate;

R₄ is —OT₄ or acyloxy;

R₉ is hydrogen, keto, —OT₉, or acyloxy;

R₁₃ is hydroxy, protected hydroxy, keto, or

R₁₄ is hydrogen, —OT₁₄, acyloxy or together with R₁ forms a carbonate;

T₂, T₄, T₉, and T₁₄ are independently hydrogen or hydroxy protectinggroup;

X₁ is —OX₆, —SX₇, or —NX₈X₉;

X₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;

X₃ and X₄ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heteroaryl;

X₅ is —X₁₀, —OX₁₀, —SX₁₀, —NX₈X₁₀, or —SO₂X₁₁;

X₆ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, hydroxyprotecting group or a functional group which increases the watersolubility of the taxane derivative;

X₇ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or sulfhydrylprotecting group;

X₈ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

X₉ is an amino protecting group;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heteroaryl;

X₁₁ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, —OX₁₀, or—NX₈X₁₄; and

X₁₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl.

Selective C(10) Derivatization

In accordance with the process of the present invention, it has beendiscovered that the C(10) hydroxyl group of a taxane can be selectivelyacylated in the absence of an amine base. Preferably, therefore, aminebases such as pyridine, triethylamine, dimethylaminopyridine and2,6-lutidine, if present at all, are present in the reaction mixture inrelatively low concentration. Stated another way, if an amine base ispresent in the reaction mixture, the molar ratio of the amine base tothe taxane is preferably less than 1:1, more preferably less than 10:1,and most preferably less than 100:1.

Acylating agents which may be used for the selective acylation of theC(10) hydroxyl group of a taxane include anhydrides, dicarbonates,thiodicarbonates, and isocyanates. In general, the anhydrides,dicarbonates, and thiodicarbonates correspond to structure 4 and theisocyanates correspond to structure 5:

wherein R¹ is —OR^(a), —SR¹, or R^(a); R² is —OC(O)R^(b), —OC(O)OR^(b),—OC(C)SR^(b), —OPOR^(b)R^(c), or —OS(O)₂R^(b); R³ is hydrocarbyl,substituted hydrocarbyl, or heteroaryl; and R^(a), R^(b), R^(c) areindependently hydrocarbyl, substituted hydrocarbyl, or heteroaryl. Forexample, suitable carboxylic acid anhydride acylating agents includeacetic anhydride, chloroacetic anhydride, propionic anhydride, benzoicanhydride, and other carboxylic acid anhydrides containing substitutedor unsubstituted hydrocarbyl or heteroaryl moieties; suitabledicarbonate acylating reagents include dibenzyl dicarbonate, diallyldicarbonate, dipropyl dicarbonate, and other dicarbonates containingsubstituted or unsubstituted hydrocarbyl or heteroaryl moieties; andsuitable isocyanate acylating agents include phenyl isocyanate, andother isocyanates containing substituted or unsubstituted hydrocarbyl orheteroaryl moieties. In addition, although the anhydrides, dicarbonates,and thiodicarbonates used as acylating agents may be mixed, it isgenerally preferred that they be symmetrical; that is, R¹ and R² areselected such that the molecule is symmetrical (e.g., if R¹ is R^(a), R²is —OC(O)R^(b) with R^(a) being the same as R^(b)).

While the acylation of the C(10) hydroxy group of the taxane willproceed at an adequate rate for many acylating agents, it has beendiscovered that the reaction rate may be increased by including a Lewisacid in the reaction mixture. The concentration of the Lewis acidappears not to be narrowly critical; experimental evidence obtained todate suggests it may be present in either a stoichiometric or acatalytic amount. In general, Lewis acids which may be used includetriflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB,VIIB, VIII, IIIA, IVA, lanthanides, and actinides of the Periodic Table(American Chemical Society format). Preferred Lewis acids include zincchloride, stannic chloride, cerium trichloride, cuprous chloride,lanthanum trichloride, dysprosium trichloride, and ytterbiumtrichloride. Zinc chloride or cerium trichloride is particularlypreferred when the acylating agent is an anhydride or dicarbonate.Cuprous chloride is particularly preferred when the acylating agent isan isocyanate.

The solvent for the selective acylation is preferably an etherealsolvent such as tetrahydrofuran. Alternatively, however, other solventssuch as ether or dimethoxyethane may be used.

The temperature at which the C(10) selective acylation is carried out isnot narrowly critical. In general, however, it is preferably carried outat room temperature or higher in order for the reaction to proceed at asufficiently high rate.

For purposes of illustration, acylating reactions involving dibenzyldicarbonate, diallyl dicarbonate, acetic anhydride, chloroaceticanhydride and phenyl isocyanate are illustrated in Reaction Schemes 1through 5 below. In this series of reaction schemes, the taxane which isselectively acylated at the C(10) position is 10-deacetylbaccatin III.It should be understood, however, that these reaction schemes are merelyillustrative and that other taxanes having a C(10) hydroxy group, ingeneral, and other 7,10-dihydroxytaxanes, in particular, may beselectively acylated with these and other acylating agents in accordancewith the present invention.

In another aspect of the present invention, the C(10) hydroxyl group ofa taxane may be selectively silylated. In general, the silylating agentis selected from the group consisting of silylamides and bissilyamides.Preferred silylamides and bissilyamides correspond to structures 6 and7, respectively:

wherein R_(D), R_(E), R_(F), R_(G), and R_(H) are independentlyhydrocarbyl, substituted hydrocarbyl, or heteroaryl. Preferably, thesilylating agents are selected from the group consisting oftri(hydrocarbyl)silyl-trifluoromethylacetamides and bistri(hydrocarbyl)-silyltrifluoromethylacetamides, with the hydrocarbylmoiety being substituted or unsubstituted alkyl or aryl. For example,the preferred silylamides and bissilylamides includeN,O-bis-(trimethylsilyl) trifluoroacetamide,N,O-bis-(triethylsilyl)trifluoroacetamide,N-methyl-N-triethylsilyltrifluoroacetamide, andN,O-bis(t-butyldimethylsilyl)trifluoroacetamide.

The silylating agents may be used either alone or in combination with acatalytic amount of a base such as an alkali metal base. Alkali metalamides, such as lithium amide catalysts, in general, and lithiumhexamethyldisilazide, in particular, are preferred.

The solvent for the selective silylation reaction is preferably anethereal solvent such as tetrahydrofuran. Alternatively, however, othersolvents such as ether or dimethoxyethane may be used.

The temperature at which the C(10) selective silylation is carried outis not narrowly critical. In general, however, it is carried out at 0°C. or greater.

Selective C(10) silylation reactions involvingN,O-bis(trimethylsilyl)trifluoroacetamide andN,O-bis(triethylsilyl)trifluoroacetamide are illustrated in ReactionSchemes 6 and 7 below. In these reaction schemes, the taxane which isselectively silylated at the C(10) position is 10-deacetylbaccatin III.It should be understood, however, that these reaction schemes are merelyillustrative and that other taxanes, having a C(10) hydroxy group, ingeneral, and other 7,10-dihydroxytaxanes, in particular, may beselectively silylated with these and other silylating agents inaccordance with the present invention.

After the C(10) hydroxyl group of a 7,10-dihydroxytaxane has beenderivatized as described herein, the C(7) hydroxyl group can readily beprotected or otherwise derivatized selectively in the presence of theC(1) and C(13) hydroxyl groups (and a C(14) hydroxy group, if present).

Selective C(7) Derivatization

Selective acylation of the C(7) hydroxyl group of a C(10) acylated orsilylated taxane can be achieved using any of a variety of commonacylating agents including, but not limited to, substituted andunsubstituted carboxylic acid derivatives, e.g., carboxylic acidhalides, anhydrides, dicarbonates, isocyanates and haloformates. Forexample, the C(7) hydroxyl group of baccatin III,10-acyl-10-deacetylbaccatin III or 10-trihydrocarbylsilyl-10-deacetylbaccatin III can be selectively acylated with dibenzyl dicarbonate,diallyl dicarbonate, 2,2,2-trichloroethyl chloroformate, benzylchloroformate or another common acylating agent.

In general, acylation of the C(7) hydroxy group of a C(10) acylated orsilylated taxane are more efficient and more selective than are C(7)acylations of a 7,10-dihydroxy taxane such as 10-DAB, i.e., once theC(10) hydroxyl group has been acylated or silylated, there is asignificant difference in the reactivity of the remaining C(7), C(13),and C(1) hydroxyl groups (and the C(14) hydroxyl group, if present).These acylation reactions may optionally be carried out in the presenceor absence of an amine base.

Examples of selective C(7) acylation of a taxane having an acylated orsilylated C(10) hydroxy group are shown in Reaction Schemes 8 through11. In these reaction schemes, the taxane which is selectively acylatedat the C(7) position is baccatin III or10-triethylsilyl-10-deacetylbaccatin III. It should be understood,however, that these reaction schemes are merely illustrative and thattaxanes having other acyl and silyl moieties at C(10) as well as othersubstituents at other taxane ring positions may be selectively acylatedat C(7) with these and other acylating agents in accordance with thepresent invention.

Alternatively, the C(7) hydroxyl group of a C(10) acylated taxanederivative can be selectively protected using any of a variety ofhydroxy protecting groups, such as acetal, ketal, silyl, and removableacyl protecting groups. For example, the C(7) hydroxyl group may besilylated using any of a variety of common silylating agents including,but not limited to, tri(hydrocarbyl)silyl halides andtri(hydrocarbyl)silyl triflates. The hydrocarbyl moieties of thesecompounds may be substituted or unsubstituted and preferably aresubstituted or unsubstituted alkyl or aryl. For example, the C(7)hydroxyl group of baccatin III can be selectively silylated usingsilylating agents such as tribenzylsilyl chloride, trimethylsilylchloride, triethylsilyl chloride, dimethyl isopropylsilyl chloride,dimethyl phenylsilyl chloride, and the like.

In general, silylations of the C(7) hydroxy group of a C(10) acylatedtaxanes are more efficient and more selective than are silylations of a7,10-dihydroxy taxane such as 10-DAB, i.e., once the C(10) hydroxylgroup has been acylated, there is a significant difference in thereactivity of the remaining C(7), C(13), and C(1) hydroxyl groups (andthe C(14) hydroxyl group, if present). The C(7) silylation reaction maybe carried out under a wide range of conditions, including in thepresence or absence of an amine base.

Examples of selective C(7) silylation of C(10) acylated taxanes areshown in Reaction Schemes 12 through 15. In these reaction schemes, thetaxane which is selectively silylated at the C(7) position is baccatinIII or another C(10)-acyloxy derivative of 10-deacetylbaccatin III. Itshould be understood, however, that these reaction schemes are merelyillustrative and that other taxanes may be selectively silylated withthese and other silylating agents in accordance with the presentinvention.

Alternatively, the C(7) hydroxyl group of C(10) acylated taxanes can beselectively protected using any of a variety of common reagentsincluding, but not limited to, simple acetals, ketals and vinyl ethers,in the presence of an acid catalyst. These reagents (whether acetal,ketal, vinyl ether or otherwise) are referred to herein as “ketalizingagents” and are described in “Protective Groups in Organic Synthesis” byT. W. Greene, John Wiley and Sons, 1981. The acid catalyst used may bean organic or inorganic acid, such as toluenesulfonic acid orcamphorsulfonic acid, in at least a catalytic amount. For example, theC(7) hydroxyl group of baccatin III can be selectively ketalized using2-methoxy propene. Other suitable reagents for the preparation ofacetals and ketals include methyl vinyl ether, ethyl vinyl ether,tetrahydropyran, and the like.

Selective ketalization of the C(7) substituent of a C(10) acylatedtaxane is more efficient and more selective than it is with 10-DAB,i.e., once the C(10) hydroxyl group has been acylated, there is a largedifference in the reactivity of the remaining C(7), C(13), and C(1)hydroxyl groups (and the C(14) hydroxyl group, if present).

An example of selective formation of a C(7) ketal from baccatin III isillustrated in Reaction Scheme 16. It should be understood, however,that this reaction scheme is merely illustrative and that other taxanesmay be selectively ketalized with this and other ketalizing agents inaccordance with the present invention.

Under appropriate conditions, the C(7) hydroxyl group of a taxanefurther comprising a C(10) hydroxyl group can be selectively silylated.Advantageously, these silylations are not limited to silyl groupsbearing alkyl substituents having three carbons or less.

In general, the C(7) hydroxyl group of a taxane can be selectivelysilylated with a silylating agent which includes the —SiR_(J)R_(K)R_(L)moiety wherein R_(J), R_(K) and R_(L) are independently substituted orunsubstituted hydrocarbyl or heteroaryl, provided that any substituentsare other than hydroxyl. In one embodiment of the present invention, ifeach of R_(J), R_(K) and R_(L) is alkyl, then at least one of R_(j),R_(k), and R_(L) comprises a carbon skeleton (i.e., carbon chain orring(s)) having at least four carbon atoms. Suitable silylating agentsinclude silyl halides and silyl triflates, for example,tri(hydrocarbyl)silyl halides and tri(hydrocarbyl)silyl triflates. Thehydrocarbyl substituents of these silylating agents may be substitutedor unsubstituted and preferably are substituted or unsubstituted alkylor aryl.

The selective silylation of the C(7) hydroxy group may be carried out ina solvent, such as dimethyl formamide (“DMF”) or pyridine and in thepresence of an amine base, such as imidazole or pyridine. ReactionSchemes 17-20 illustrate the silylation of the C(7) hydroxy group of10-DAB in high yield by treating 10-DAB with t-butyldimethylsilylchloride, tribenzylsilyl chloride, dimethyl-isopropylsilyl chloride, anddimethylphenylsilyl chloride, respectively. Silylation under theseconditions was surprising in view of the report by Denis, et. al. (J.Am. Chem. Soc., 1988, 110, 5917) that selective formation of7-TBS-10-DAB was not possible.

The process of the present invention can also be used to protect theC(7) and C(10) hydroxy groups of a 7,10-dihydroxytaxane with differentsilyl protecting groups. By selecting groups which can be removed underdifferent conditions, the C(7) and C(10) hydroxy groups can beseparately accessed for derivatization. These reactions, therefore,increase the flexibility of the overall process and, enable a higheryield for many of the individual protecting reactions relative to theyield obtained using currently available processes. For example, thetriethylsilyl protecting group is more readily removed from C(10) thanis the t-butyldimethylsilyl protecting group from C(7) and thedimethylphenylsilyl protecting group is more readily removed from C(7)than is the t-butyldimethylsilyl protecting group from C(10). Thepreparation of 7-t-butyldimethylsilyl-10-triethylsilyl-10-DAB and7-dimethylphenylsilyl-10-t-butyldimethylislyl-10-DAB are illustrated inReaction Schemes 21 and 22.

The methods disclosed herein may be used in connection with a largenumber of different taxanes obtained from natural or synthetic sourcesto prepare a wide variety of taxane intermediates which may then befurther derivatized. For example, the methods of the present inventionmay be effectively used to protect the C(7) and/or C(10) hydroxyfunctional group prior to the coupling reaction between a C(13) sidechain precursor and a taxane to introduce a C(13) β-amido ester sidechain, and also prior to the reactions for preparing taxanes havingalternative substituents at various locations on the taxane nucleus.

The attachment of a C(13) side chain precursor to a taxane may becarried out by various known techniques. For example, a side chainprecursor such as an appropriately substituted β-lactam, oxazoline,oxazolidine carboxylic acid, oxazolidine carboxylic acid anhydride, orisoserine derivative may be reacted with a tricyclic or tetracyclictaxane having a C(13) hydroxy, metallic oxide or ammonium oxidesubstituent to form compounds having a β-amido ester substituent atC(13) as described, for example, Taxol: Science and Applications, M.Suffness, editor, CRC Press (Boca Rotan, Fla.) 1995, Chapter V, pages97-121. For example, the synthesis of taxol from 10-DAB is illustratedin reaction scheme 23. It should be noted that while a β-lactam and10-DAB are used in this reaction scheme, other side chain precursors andother taxanes could be substituted therefor without departing from thepresent invention.

The process illustrated in Reaction Scheme 23 is significantly moreefficient than any other currently known process, due to the high yieldsand selectivity of the cerium trichloride catalyzed acetylation of theC(10) hydroxyl group of 10-DAB and the subsequent silylation of the C(7)hydroxyl group. The synthesis proceeds in four steps and 89% overallyield.

Reaction schemes 24 and 25 illustrate the preparation of taxanes havingsubstituents appended to the C(7) hydroxyl group and a free C(10)hydroxyl group. The method of the current invention provides flexibilityso that the substituent attached to the C(7) hydroxyl group can be putin place either before or after attachment of the C(13) side chain.

Reaction scheme 24 outlines the preparation of a taxane which has beenfound to be a potent chemotherapeutic radiosensitizer, illustratingattachment of the substituent at the C(7) hydroxyl group beforeintroduction of the C(13) side chain. According to the process ofreaction scheme 7,10-DAB is first converted to 10-TES-10-DAB. The C(7)hydroxyl group is then converted to an intermediate imidazolide bytreatment with carbonyl diimidazole, and the intermediate imidazolidesubsequently reacts, without isolation, with metronidazole alcohol toprovide 7-metro-10-TES-10-DAB. Coupling of 7-metro-10-TES-10-DAB with aβ-lactam to introduce the side chain at C(13) is followed by removal ofthe TES groups at C(10) and C(2′) by treatment with HF and pyridine.

Reaction scheme 25 outlines the preparation of a taxane useful inidentifying proteins which form bioconjugates with taxanes. Itillustrates a protocol for attachment of a substituent at the C(7)hydroxyl group after introduction of the C(13) side chain. According tothe processes of reaction schemes 7 and 11, 10-DAB is first converted to7-p-nitrobenzyloxycarbonyl-10-TES-10-DAB. The C(13) side chain isattached employing a TES protected β-lactam, and thep-nitrobenzyloxycarbonyl protecting group is then selectively removed bytreatment with hydrogen and a palladium catalyst, producing2′,10-(bis)-TES-taxotere. The C(7) hydroxyl group then reacts withcarbonyl diimidazole and the derived imidazolide is treated with1,4-diamino butane to give a primary amine. Reaction of the primaryamine with the hydroxysuccinimide ester of biotin completes theattachment of the biotinamide group at C(7). Finally, treatment with HFin pyridine solution removes the TES protecting groups at C(10) andC(2′).

The protected taxane derivatives or the intermediates or startingmaterials used in the preparation of such protected taxane derivativescan be further modified to provide for alternative substituents atvarious positions of the taxane.

Taxanes having C(2) and/or C(4) substituents other than benzoyloxy andacetoxy, respectively, can be prepared from baccatin III, 10-DAB andother taxanes as more fully described in PCT Patent Application WO94/01223. In general, the C(2) and C(4) acyloxy substituents are treatedwith lithium aluminum hydride or another suitable reducing agent to fromhydroxy groups at C(2) and C(4) which may then be reacted, for example,with carboxylic acid halides (optionally after protection of the C(2)hydroxy group together with the C(1) hydroxy group with a 1,2-carbonateprotecting group) to obtain the desired C(2) and C(4) derivatives.

Taxanes having C(7) substituents other than hydroxy and acyloxy asdescribed herein can be prepared from baccatin III, 10-DAB, and othertaxanes as more fully described in PCT Patent Application WO 94/17050.For example, a C(7) xanthate may be subjected to tin hydride reductionto yield the corresponding C(7) dihydro taxane. Alternatively, C(7)fluoro-substituted taxanes can be prepared by treatment ofC(13)-triethylsilyl-protected baccatin III with2-chloro-1,1,2-trifluorotriethylamine at room temperature in THFsolution. Other baccatin derivatives with a free C(7) hydroxyl groupbehave similarly. Alternatively, 7-chloro baccatin III can be preparedby treatment of baccatin III with methanesulfonyl chloride andtriethylamine in methylene chloride solution containing an excess oftriethylamine hydrochloride.

Taxanes having C(9) substituents other than keto can be prepared frombaccatin III, 10-DAB and other taxanes as more fully described in PCTPatent Application WO 94/20088. In general, the C(9) keto substituent ofthe taxane is selectively reduced to yield the corresponding C(9)β-hydroxy derivative with a borohydride, preferably tetrabutylammoniumborohydride (Bu₄NBH₄) or triacetoxy-borohydride. The C(9) β-hydroxyderivative can then be protected at C(7) with a hydroxy protecting groupand the C(9) hydroxy group can be acylated following the methodsdescribed herein for acylation of the C(7) hydroxy group. Alternatively,reaction of 7-protected-9β-hydroxy derivative with KH causes the acetategroup (or other acyloxy group) to migrate from C(10) to C(9) and thehydroxy group to migrate from C(9) to C(10), thereby yielding a10-desacetyl derivative, which can be acylated as described elsewhereherein.

Taxanes having C(10) substituents other than hydroxy, acyloxy orprotected hydroxy as described herein may be prepared as more fullydescribed in PCT Patent Application WO 94/15599 and other literaturereferences. For example, taxanes having a C(10) keto substituent can beprepared by oxidation of 10-desacetyl taxanes. Taxanes which are dihydrosubstituted at C(10) can be prepared by reacting a C(10) hydroxy oracyloxy substituted taxane with samarium diiodide.

Taxanes having a C(14) substituent other than hydrogen may also beprepared. The starting material for these compounds may be, for example,a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) which hasbeen discovered in an extract of yew needles (C&EN, p 36-37, Apr. 12,1993). Derivatives of this hydroxylated taxane having the various C(2),C(4), C(7), C(9), C(10), C3′ and C5′ functional groups described abovemay also be prepared by using this hydroxylated taxane. In addition, theC(14) hydroxy group together with the C(1) hydroxy group of 10-DAB canbe converted to a 1,2-carbonate-as described in C&EN or it may beconverted to a variety of esters or other functional groups as otherwisedescribed herein in connection with the C(2), C(4), C(9) and C(10)substituents.

The process of the present invention thus enables the preparation oftaxanes having the following structure:

wherein

M comprises ammonium or is a metal;

R₁ is hydrogen, hydroxy, protected hydroxy, or together with R₁₄ or R₂forms a carbonate;

R₂ is keto, —OT₂, acyloxy, or together with R₁ forms a carbonate;

R₄ is —OT₄ or acyloxy;

R₇ is hydrogen, halogen, —OT₇, or acyloxy;

R₉ is hydrogen, keto, —OT₉, or acyloxy;

R₁₀ is hydrogen, keto, —OT₁₀, or acyloxy;

R₇, R₉, and R₁₀, independently have the alpha or beta stereochemicalconfiguration;

R₁₃ is hydroxy, protected hydroxy, keto, MO— or

R₁₄ is hydrogen, —OT₁₄, acyloxy, or together with R₁ forms a carbonate;

T₂, T₄, T₇, T₉, T₁₀ and T₁₄ are independently hydrogen or hydroxyprotecting group;

X₁ is —OX₆, —SX₇, or —NX₈X₉;

X₂ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;

X₃ and X₄ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or heteroaryl;

X₅ is —X₁₀, —OX₁₀, —SX₁₀, —NX₈X₁₀, or —SO₂X₁₁;

X₆ is hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl,hydroxy protecting group, or a functional group which increases thewater solubility of the taxane derivative;

X₇ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or sulfhydrylprotecting group;

X₈ is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

X₉ is an amino protecting group;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heteroaryl;

X₁₁ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, —OX₁₀, or—NX₈X₁₄;

X₁₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl.

In one embodiment of the present invention, the substituents of thetaxane (other than the C(7), C(10) and C(13) substituents) correspond tothe substituents present on baccatin III or 10-DAB. That is, R₁₄ ishydrogen, R₉ is keto, R₄ is acetoxy, R₂ is benzoyloxy, and R₁ ishydroxy. In other embodiments, the taxane has a structure which differsfrom that of taxol or Taxotere® with respect to the C(13) side chain andat least one other substituent. For example, R,₄ may be hydroxy; R₂ maybe hydroxy, —OCOZ₂ or —OCOOZ₂₂ wherein Z₂ is hydrogen, hydrocarbyl,substituted hydrocarbyl, or heteroaryl and Z₂₂ is hydrocarbyl,substituted hydrocarbyl, or heteroaryl; R₄ may be hydroxy, —OCOZ₄ or—OCOOZ₄₄ wherein Z₄ is hydrogen, hydrocarbyl, substituted hydrocarbyl,or heteroaryl and Z₄₄ is hydrocarbyl, substituted hydrocarbyl, orheteroaryl; R₇ may be hydrogen, hydroxy, —OCOZ₇ or —OCOOZ₇₇ wherein Z₇is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z₇₇is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl, R₉ maybe hydrogen, hydroxy, —OCOZ₉ or —OCOOZ₉₉ wherein Z₉ is hydrogen,hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z₉₉ is hydrogen,hydrocarbyl, substituted hydrocarbyl, or heteroaryl, and R₁₀ may behydrogen, hydroxy, —OCOZ₁₀ or —OCOOZ₁₀₁₀ wherein Z₁₀ is hydrogen,hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z₁₀₁₀ ishydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl.

In a preferred embodiment, the taxane has the formula

wherein P₁₀ is acyl, said acyl comprising at least three carbon atoms ortwo carbon atoms and a nitrogen, oxygen or sulfur atom. Stated anotherway, —OP₁₀ is other than acetoxy. More preferably, P₁₀ is —(C═O)R_(A),—(C═O)OR_(B), or —(C═O)NR_(C) wherein R_(A) is substituted orunsubstituted hydrocarbyl or heteroaryl, said unsubstituted hydrocarbylcomprising at least two carbon atoms; R_(B) and R_(C) are independentlysubstituted or unsubstituted hydrocarbyl. Still more preferably, R_(A)is substituted or unsubstituted alkyl or aryl, said unsubstituted alkylcomprising at least two carbon atoms; and R_(B) and R_(C) areindependently substituted or unsubstituted alkyl or aryl.

In another embodiment of the invention, the taxane has the formula

wherein P₇ and P₁₀ are independently substituted or unsubstituted acyl.In this embodiment, P₇ and P10 are preferably different.

DEFINITIONS

As used herein, the terms “selective” and “selective derivatization”shall mean that the desired product is preferentially formed over anyother by-product. Preferably, the desired product is present in a molarratio of at least 9:1 relative to any other by-product and, morepreferably, is present in a molar ratio of at least 20:1 relative to anyother by-product.

In addition, “Ph” means phenyl; “Bz” means benzoyl; “Bn” means benzyl;“Me” means methyl; “Et” means ethyl; “iPr” means isopropyl; “tBu” and ”t-Bu” means tert-butyl; “Ac” means acetyl; “TES” means triethylsilyl;“TMS” means trimethylsilyl; “TBS” means Me₂t-BuSi—; “CDI” means carbonyldiimidazole; “BOM” means benzyloxymethyl; “DBU” meansdiazabicycloundecane; “DMAP” means p-dimethylamino pyridine; “LHMDS” or“LiHMDS” means lithium hexamethyldisilazide; “DMF” meansdimethylformamide; “10-DAB” means 10-desacetylbaccatin III; “Cbz” meansbenzyloxycarbonyl; “Alloc” means allyloxycarbonyl; “THF” meanstetrahydrofuran; “BOC” means benzyloxycarbonyl; “PNB” meanspara-nitrobenzyl; “Troc” means 2,2,2-trichloroethoxycarbonyl; “EtOAc”means ethyl acetate; “THF” means tetrahydrofuran; “protected hydroxyl”means —OP wherein P is a hydroxyl protecting group; and “hydroxylprotecting group” includes, but is not limited to, acetals having two toten carbons, ketals having two to ten carbons, and ethers, such asmethyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl,methbxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxy propyl,tetrahydropyranyl, tetrahydrothiopyranyl; and trialkylsilyl ethers suchas trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether,triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such asbenzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetylsuch as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl;and carbonates including but not limited to alkyl carbonates having fromone to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having fromone to six carbon atoms and substituted with one or more halogen atomssuch as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates having from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl protecting groups may be found in“Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley andSons, 1981, and Second Edition, 1991.

The “hydrocarbon” and “hydrocarbyl”, moieties described herein areorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbylgroups, and include alkaryl, alkenaryl and alkynaryl. Preferably, thesemoieties comprise 1 to 20 carbon atoms.

The alkyl groups described herein are preferably lower alkyl containingfrom one to six carbon atoms in the principal chain and up to 20 carbonatoms. They may be straight, branched chain or cyclic and includemethyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may besubstituted with aliphatic or cyclic hydrocarbyl radicals.

The alkenyl groups described herein are preferably lower alkenylcontaining from two to six carbon atoms in the principal chain and up to20 carbon atoms. They may be straight or branched chain and includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and thelike. They may be substituted with aliphatic or cyclic hydrocarbylradicals.

The alkynyl groups described herein are preferably lower alkynylcontaining from two to six carbon atoms in the-principal chain and up to20 carbon atoms. They may be straight or branched chain and includeethynyl, propynyl, butynyl, isobutenyl, hexynyl, and the like. They maybe substituted with aliphatic or cyclic hydrocarbyl radicals.

The aryl moieties described herein contain from 6 to 20 carbon atoms andinclude phenyl. They may be hydrocarbyl substituted with the varioussubstituents defined herein. Phenyl is the more preferred aryl.

The heteroaryl moieties described are heterocyclic compounds or radicalswhich are analogous to aromatic compounds or radicals and which containa total of 5 to 20 atoms, usually 5 or 6 ring atoms, and at least oneatom other than carbon, such as furyl, thienyl, pyridyl and the like.The heteroaryl moieties may be substituted with hydrocarbyl,heterosubstituted hydrocarbyl or hetero-atom containing substituentswith the hetero-atoms being selected from the group consisting ofnitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens.These substituents include hydroxy; lower alkoxy such as methoxy,ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals;ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; acyl;acyloxy; nitro; amino; and amido.

The substituted hydrocarbyl moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbonand hydrogen, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude hydroxy; lower alkoxy such as methoxy, ethoxy, butoxy; halogensuch as chloro or fluoro; ethers; acetals; ketals; esters; heteroarylsuch as furyl or thienyl; alkanoxy; acyl; acyloxy; nitro; amino; andamido.

The acyl moieties and the acyloxy moieties described herein containhydrocarbyl, substituted hydrocarbyl or heteroaryl moieties. In general,they have the formulas —C(O)G and —OC(O)G, respectively, wherein G issubstituted or unsubstituted hydrocarbyl, hydrocarbyloxy,hydrocarbylamino, hydrocarbylthio or heteroaryl.

The ketal moieties described herein have the general formula

wherein X³¹, X³², X³³ and X³⁴ are independently hydrocarbyl, substitutedhydrocarbyl or heteroaryl moieties. They may be optionally substitutedwith the various substituents defined herein. The ketal moieties arepreferably substituted or unsubstituted alkyl or alkenyl, and morepreferably substituted or unsubstituted lower (C₁-C₆) alkyl. These ketalmoieties additionally may encompass sugars or substituted sugars andinclude ketal moieties prepared from sugars or substituted sugars suchas glucose and xylose. When a ketal moiety is incorporated into a taxaneof the present invention as a C(7) hydroxy protecting group, then eitherX³¹ or X³² represents the taxane moiety.

The acetal moieties described herein have the general formula

wherein X³¹, X³² and X³³ are independently hydrocarbyl, substitutedhydrocarbyl or heteroaryl moieties. They may be optionally substitutedwith the various substituents defined herein other than hydroxyl. Theacetal moieties are preferably substituted or unsubstituted alkyl oralkenyl, and more preferably substituted or unsubstituted lower (C₁-C₆)alkyl. These acetal moieties additionally may encompass sugars orsubstituted sugars and include acetal moieties prepared from sugars orsubstituted sugars such as glucose and xylose. When an acetal moiety isincorporated into a taxane of the present invention as a C(7) hydroxyprotecting group, then either X³¹ or X³² represents the taxane moiety.

The term “taxane” as used herein, denotes compounds containing the A, Band C rings (with numbering of the ring positions shown herein):

The following examples illustrate the invention.

EXAMPLE 1

A. Selective Acylation of a C(10) Hydroxyl Group:

10-Cbz-10-DAB. To a solution of 10-DAB (30 mg, 0.055 mmol) in THF (1 mL)at room temperature was added dibenzyl pyrocarbonate (320 mg, 1.1 mmol,20 equiv) under N₂. The reaction mixture was stirred at room temperaturefor 24 h. EtOAc (10 mL) was added, and the solution was quickly filteredthrough a short column of silica gel. The silica gel was washed withEtOAc (100 mL), and the solution was concentrated under reducedpressure. The residue was purified by flash column chromatography usingEtOAc: hexanes (1:1) as the eluent and dried in vacuo overnight to give10-cbz-10-DAB as a colorless solid: yield, 37 mg (98%). mp 205-206° C.;[α]_(Hg) −63° (CHCl₃, c=0.41); ¹H NMR (400 MHz, CDCl₃) δ 1.11(s, 3 H,Me17), 1.13(s, 3 H, Me16), 1.58(s, 1 H, 1-OH), 1.71(s, 3 H, Me19),1.89(ddd, J=14.7, 10.9, 2.3 Hz, 1 H, H6b), 2.00(d, J=5.1 Hz, 1 H,13-OH), 2.08(d, J=1.0, 3 H, Me18), 2.28(s, 3 H, 4-Ac), 2.30(m, 2 H,H14a, H14b), 2.43(d, J=4.1 Hz, 1 H, 7-OH), 2.58(ddd, J=14.7, 9.6, 6.6Hz, 1 H, H6a), 3.88(d, J=6.9 Hz, 1 H, H3), 4.19(d, J=8.6 Hz, 1 H, H20b),4.31(d, J=8.6 Hz, 1 H, H20a), 4.44(ddd, J=10.9, 6.6, 4.1 Hz, 1 H, H7),4.89(m, 1 H, H13), 4.98(dd, J=9.6, 2.3 Hz, 1 H, H5), 5.23(d, J=12.1, 1H, CHH′OC(O)), 5.26(d, J=12.1, 1 H, CHH′OC(O)), 5.65(d, J=6.9 Hz, 1 H,H2), 6.19(s, 1 H, H10), 7.35-7.44(m, 5 H, PhCH₂O), 7.48(dd, J=8.1, 7.6Hz, 2 H, benzoate, m), 7.60(tt, J=7.6, 1.0 Hz, 1 H, benzoate, p),8.11(d, J=8.1, 1.0 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ9.1(Me(19)), 15.3(Me(18)), 20.7(4-Ac), 22.3, 26.7(Me16, Me17),35.5(C(6)), 38.6(C(14)), 42.5(C(15)), 46.1(C(3)), 58.7(C(8)),67.9(C(13)), 70.5(OCH₂Ph), 72.2, 75.0, 76.5(C(7), C(2), C(20)), 79.0,79.1 (C(1), C(10)), 80.9(C(4)), 84.5(C(5)), 128.6, 128.8, 129.7, 130.3,131.9, 133.8(OCH₂Ph, benzoate), 135.1(C(11)), 147.5(C(12)),155.6(OC(O)O), 167.4(benzoate), 171.0(4-Ac), 204.7(C(9))ppm. Anal. Calcdfor C₃₇H₄₂O₁₂. 1/2H₂O: C, 64.62; H, 6.30. Found: C, 64.34; H, 6.31.

10-Alloc-10-DAB. To a solution of 10-DAB (30 mg, 0.055 mmol) in THF (1mL) at room temperature was added diallyl pyrocarbonate (366 mL, 2.2mmol, 40 equiv) under N₂. The reaction mixture was stirred at roomtemperature for 48 h. TLC analysis indicated the presence of the desiredproduct along with unreacted staring material. EtOAc (20 mL) was added,and the solution was quickly filtered through a short column of silicagel. The silica gel was washed with EtOAc (100 mL), and the solution wasconcentrated. The residue was purified by flash column chromatographyusing EtOAc: hexanes (1:1) as the eluent and dried in vacuo to overnightto give 10-alloc-10-DAB as a colorless solid: yield, 23 mg (67%, 95% atthe conversion of 70%). The recovered 10-DAB, 9 mg (30%).10-alloc-10-DAB: mp 201-203° C.; [α]_(Hg) −81° (CHCl₃, c=0.53); ¹H NMR(400 MHz, CDCl₃) δ 1.11(s, 3 H, Me17), 1.12(s, 3 H, Me16), 1.60(s, 1 H,1-OH), 1.69(s, 3 H, Me19), 1.87(ddd, J=14.7, 11.0, 2.1 Hz, 1 H, H6b),2.05(d, J=5.1 Hz, 1 H, 13-OH), 2.08(d, J=1.2, 3 H, Me18), 2.28(s, 3 H,4-Ac), 2.29(m, 2 H, H14a, H14b), 2.47(d, J=4.2 Hz, 1 H, 7-OH), 2.57(ddd,J=14.7, 9.6, 6.7 Hz, 1 H, H6a), 3.86(d, J=7.0 Hz, 1 H, H3), 4.16(d,J=8.4 Hz, 1 H, H20b), 4.31(d, J=8.4 Hz, 1 H, H20a), 4.44(ddd, J=11.0,6.7, 4.2 Hz, 1 H, H7), 4.70(br d, J=5.9 Hz, 2 H, CHH′═CHCH₂O), 4.90(m, 1H, H13), 4.97(dd, J=9.6, 2.1 Hz, 1 H, H5), 5.32(dd, J=10.4, 1.2 Hz, 1 H,CHH′═CHCH₂O), 5.42(dd, J=17.2, 1.2 Hz, 1 H, CHH′═CHCH₂O), 5.63(d, J=7.0Hz, 1 H, H2), 5.98(ddt, J=17.2, 10.4, 5.9 Hz, 1 H, CHH′═CHCH₂O), 6.16(s, 1 H, H10), 7.48(dd, J=8.1, 7.5 Hz, 2 H, benzoate, m), 7.60(tt,J=7.5, 1.2 Hz, 1 H, benzoate, p), 8.11(d, J=8.1, 1.2 Hz, 2 H, benzoate,o) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 9.1(Me(19)), 15.3(Me(18)), 20.7(4-Ac),22.3, 26.7(Me16, Me17), 35.5(C(6)), 38.6(C(14)), 42.5(C(15)),46.1(C(3)), 58.7(C(8)), 67.9(C(13)), 69.3(CH₂═CHCH₂O), 72.1, 75.0,76.5(C(7), C(2), C(20)), 79.0, 79.1(C(1), C(10)), 80.9(C(4)),84.5(C(5)), 119.6(CH₂═CHCH₂O), 128.8, 129.7, 130.3, 133.8(benzoate),131.4, 131.9(CH₂═CHCH₂O, C(11)) 147.5 (C(12)), 155.4 (OC(O)O), 167.4(benzoate), 170.9(4-Ac), 204.7(C(9))ppm. Anal. Calcd for C₃₃H₄₀O₁₂: C,63.05; H, 6.41. Found: C, 62.77; H, 6.48.

B. Selective Acylation of a C(10) Hydroxyl Group using ZnCl₂:

baccatin III. To a solution of 10-DAB (100 mg, 0.184 mmol) in THF (6 mL)at room temperature was added a mixture of acetic anhydride (6.5 mL) andZnCl₂/THF solution (0.5 M, 726 mL, 0.368 mmol, 2 equiv) under N₂. Thereaction mixture was stirred at room temperature for 4 h. Then thereaction mixture was diluted with EtOAc (100 mL), washed with saturatedaqueous NaHCO₃ solution (40 mL×3), brine. The organic layer was driedover Na₂SO₄, concentrated under reduced pressure. The residue waspurified by flash column chromatography using EtOAc: hexanes (1:1) asthe eluent and dried in vacuo to give baccatin III as a colorless solid:yield, 100 mg (93%). mp 237-238° C. dec (ref 236-238° C. dec); [α]_(Hg)−63° (CH₃OH, c=0.45) (ref [α]_(D) −540, CH₃OH); ¹H NMR (400 MHz, CDCl₃)δ 1.11(s, 6 H, Me16, Me17), 1.61(s, 1 H, 1-OH), 1.67(s, 3 H, Me19),1.87(ddd, J=14.7, 10.9, 2.1 Hz, 1 H, H6b), 2.05(d, J=3.8 Hz, 1 H,13-OH), 2.05(s, 3 H, Me18), 2.24(s, 3 H, 10-Ac), 2.28(s, 3 H, 4-Ac),2.30(m, 2 H, H14a, H14b), 2.47(d, J=4.2 Hz, 1 H, 7-OH), 2.57(ddd,J=14.7, 9.4, 6.7 Hz, 1 H, H6a), 3.89(d, J=7.0 Hz, 1 H, H3), 4.16(d,J=8.4 Hz, 1 H, H20b), 4.31(d, J=8.4 Hz, 1 H, H20a), 4.47(ddd, J=10.9,6.7, 4.2 Hz, 1 H, H7), 4.90(m, 1 H, H13), 4.99(dd, J=9.4, 2.1 Hz, 1 H,H5), 5.63(d, J=7.0 Hz, 1 H, H2), 6.33(s, 1 H, H10), 7.48(dd, J=7.8, 7.8Hz, 2 H, benzoate, m), 7.61(dd, J=7.8, 7.4 Hz, 1 H, benzoate, p),8.11(d, J=7.4 Hz, 2 H, benzoate, o)ppm. ¹³C NMR (100 MHz, CDCl₃) 679.4(Me(19)), 15.6(Me(18)), 20.9(4-Ac, 10-Ac), 22.6, 27.0(Me16, Me17),35.6 (C(6)), 38.6 (C(14)), 42.7 (C(15)), 46.1 (C(3)), 58.8(C(8)),68.0(C(13)), 72.3, 75.0, 76.2, 76.4(C(7), C(2), C(10), C(20)),79.1(C(1)), 80.9(C(4)), 84.5(C(5)) 128.6, 129.4, 130.1, 133.7(benzoate),132.0(C(11)), 146.3(C(12)), 167.1(benzoate), 170.7, 171.3(10-Ac, 4-Ac),204.1 (C(9))ppm.

10-Chloroacetyl-10-DAB. To a solution of 10-DAB (116 mg, 0.21 mmol) inTHF (3 mL) at room temperature was added a mixture of chloroaceticanhydride (2.8 g, 16.3 mmol, 78 equiv) and ZnCl₂/THF solution (0.5 M,0.85 mL, 0.42 mmol, 2 equiv) via a syringe under N₂. The reactionmixture was stirred at room temperature for 5 h. The reaction mixturewas poured into a mixture of EtOAc (200 mL) and saturated aqueous NaHCO₃solution (100 mL). The organic layer was separated, and the aqueouslayer was extracted with EtOAc (100 mL×3). The organic solution wascombined, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography usingEtOAc: hexanes (1:1) as the eluent and dried overnight in vacuo to give10-chloro-acetyl-10-DAB as a colorless solid: yield, 123 mg (93%). mp231-233° C. dec; [α]_(Hg) −66° (EtOAc, c=0.45); ¹H NMR (400 MHz, CDCl₃)δ 1.11 (s, 3 H, Me17) 1.12(s, 3 H, Me16), 1.63(s, 1 H, 1-OH), 1.69(s, 3H, Me19), 1.89(ddd, J=14.6, 10.9, 2.1 Hz, 1 H, H6b), 2.07(d, J=5.2 Hz, 1H, 13-OH), 2.09(d, J=1.2, 3 H, Me18), 2.12(d, J=4.5 Hz, 1 H, 7-OH),2.29(s, 3 H, 4-Ac), 2.30(m, 2 H, H14a, H14b), 2.58(ddd, J=14.6, 9.7, 6.7Hz, 1 H, H6a), 3.88(d, J=7.0 Hz, 1 H, H3), 4.16(d, J=8.3 Hz, 1 H, H20b),4.27(br s, 2 H, ClCH₂), 4.31(d, J=8.3 Hz, 1 H, H20a), 4.44(ddd, J=10.9,6.7, 4.5 Hz, 1 H, H7), 4.90(m, 1 H, H13), 4.98(dd, J=9.7, 2.1 Hz, 1 H,H5), 5.64(d, J=7.0 Hz, 1 H, H2), 6.41(s, 1 H, H10) 7.49(dd, J=7.9, 7.4Hz, 2 H, benzoate, m), 7.61(tt, J=7.4, 1.3 Hz, 1 H, benzoate, p),8.11(d, J=7.9, 1.3 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ9.3(Me(19)), 15.3(Me(18)), 20.6(4-Ac), 22.3, 26.7(Me16, Me17),35.8(C(6)), 38.6(C(14)), 40.5(ClCH₂), 42.6(C(15)) 46.2(C(3)),58.8(C(8)), 68.0(C(13)), 72.0, 75.0, 75.9(C(7), C(2), C(10), C(20)),79.0(C(1)), 80.9(C(4)), 84.4(C(5)), 128.8, 129.7, 130.3,133.9(benzoate), 131.8(C(11)), 147.1(C(12)), 167.4, 167.7(ClCH₂C(O)O,benzoate), 171.0(4-Ac), 203.7(C(9))ppm. Anal. Calcd for C₃₁H₃₇ClO₁₁.H₂O:C, 58.26; H, 6.15. Found: C, 58.26; H, 6.07.

10-Propionyl-10-DAB. To a solution of 10-DAB (47 mg, 0.086 mmol) in THF(2 mL) at room temperature was added a mixture of propionic anhydrideanhydride (4 mL) and ZnCl₂/THF solution (0.5 M, 350 mL, 0.173 mmol, 2equiv) under N₂. The reaction mixture was stirred at room temperaturefor 14 h. Then the reaction mixture was diluted with EtOAc (150 mL),exhaustively washed with saturated aqueous NaHCO₃ solution (50 mL×3),brine. The organic layer was dried over Na₂SO₄, concentrated underreduced pressure. The residue was purified by flash columnchromatography using EtOAc: hexanes (1:1) as the eluent and dried invacuo to give 10-propionyl-10-DAB as a white solid: yield, 48 mg (93%).mp 212-213° C. dec; [α]_(Hg) −96° (CHCl₃, c=0.78); ¹H NMR (400 MHz,CDCl₃) δ 1.11(s, 6 H, Me16, Me17), 1.24(t, J=7.6 Hz, 3 H, CH₃CH₂),1.60(s, 1 H, 1-OH), 1.67(s, 3 H, Me19), 1.87(ddd, J=14.7, 10.9, 2.2 Hz,1 H, H6b), 2.05(d, J=5.1 Hz, 1 H, 13-OH), 2.06(d, J=1.3 Hz, 3 H, Me18),2.28(s, 3 H, 4-Ac), 2.30(d, J=7.5 Hz, 2 H, H14a, H14b), 2.51(d, J=4.1Hz, 1 H, 7-OH), 2.55(q, J=7.6 Hz, 2 H, CH₃CH₂), 2.57(ddd, J=14.7, 9.5,6.7 Hz, 1 H, H6a), 3.90(d, J=6.9 Hz, 1 H, H3), 4.16(dd, J=8.4, 0.8 Hz, 1H, H20b), 4.31(d, J=8.4 Hz, 1 H, H20a), 4.48(ddd, J=10.9, 6.7, 4.1 Hz, 1H, H7), 4.90(m, 1 H, H13), 4.99(dd, J=9.5, 2.2 Hz, 1 H, H5), 5.63(d,J=6.9 Hz, 1 H, H2), 6.34(s, 1 H, H10), 7.48(dd, J=8.1, 7.4 Hz, 2 H,benzoate, m), 7.61(tt, J=7.4, 1.3 Hz, 1 H, benzoate, p), 8.11(dd, J=8.3,1.3 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 8.8 (CH₃CH₂),9.2 (Me(19)), 15.2 (Me(18)) 20.7(4-Ac), 22.3, 26.8, 27.4(Me16, Me17,CH₃CH₂) 35.5(C(6)), 38.7(C(14)), 42.6(C(15)), 46.1(C(3)), 58.7(C(8)),67.9(C(13)), 72.3, 75.1, 76.1, 76.5(C(7), C(2), C(10), C(20)),79.1(C(1)), 80.9(C(4)), 84.5(C(5)), 128.7, 129.7, 130.3,133.8(benzoate), 132.3(C(11)), 146.5(C(12)), 167.4(benzoate), 170.9,174.9(4-Ac, 10-C(O)O), 204.6(C(9))ppm. Anal. Calcd for C₃₂H₄₀O₁₁: C,63.99; H, 6.71. Found: C, 63.81; H, 6.80.

C. Selective Acylation of a C(10) Hydroxyl Group using CeCl₃:

General procedure: To a solution of 10-DAB in THF (20 mL per mmol of10-DAB) under N₂ was added CeCl₃ and the appropriate anhydride orpyrocarbonate (amounts specified in Table 1). The reaction mixture wasstirred at 25° C. and monitored by TLC analysis. When that analysisindicated complete reaction (time specified in Table 1), the reactionmixture was diluted with EtOAc and washed three times with saturatedaqueous sodium bicarbonate solution. The combined bicarbonate washingswere extracted three times with EtOAc, the organic layers were combinedand dried over sodium sulfate, and the solvent was evaporated. The crudeproduct was purified by flash column chromatography. Furtherpurification, if necessary, was carried out by recrystallization fromEtoAc/Hexane. TABLE 1 CeCl₃ catalyzed acylation of 10-DAB

Entry R (eq) CeCl₃ (eq) Time (hr) Yield (%) 1 Me (10) 0.1 1.5 91 2 Pr(10) 0.1 3 100 3 iPr (10) 0.1 4.5 100 4 Ph (10) 0.1 21 94 5 cyclopropyl(10) 0.1 20.5 94 6 MeCH═CH (10) 0.1 20 91 7 CH₂═CHCH₂O (5) 0.1 1 96 8EtO (5) 0.1 3 99 9 MeO (5) 0.1 3 98 10 tBuO (10) 0.7 24 94 11 BnO (3)0.7 1 98

10-butyryl-10-DAB. mp 145-149° C.; [α]_(Hg) −86.6° (CHCl₃, c=1); ¹H NMR(500 MHz, CDCl₃) δ 8.13-8.11 (2H, m), 7.62 (1H, m), 7.51-7.48 (2H, m),6.35 (1H, s), 5.64 (1H, d, J 7.0 Hz), 4.99 (1H, d, J 7.7 Hz), 4.90 (1H,m), 4.48 (1H, m), 4.31 (1H, d, J 8.3 Hz), 4.18 (1H, d, J 8.3 Hz, 3.91(1H, d, J 7.0 Hz), 2.60-2.42 (4H, m) 2.36-2.26 (2H, m), 2.28 (3H, s),2.06 (3H, d, J 1.0 Hz), 1.88 (1H, ddd, J 1.9, 10.9, 13.0 Hz), 1.76 (2H,hex, J 7.4 Hz, 1.68 (3H, s), 1.12 (6H, s) and 1.04 (3H, t, J 7.4 Hz);¹³C NMR (100 MHz, CDCl₃) δ 204.2, 173.9, 170.6, 167.1, 146.2, 133.7,132.0, 130.1, 129.4, 128.6, 84.5, 88.9, 79.1, 76.5, 76.0, 75.0, 72.3,68.0, 58.8, 46.2, 42.7, 38.7, 37.1, 36.2, 35.6, 30.6, 27.0, 22.6, 20.9,18.4, 17.8, 15.5 and 9.4; Anal. Calcd. for C₃₃H₄₂O₁₁: C, 64.48; H, 6.89Found: C, 63.67; H, 7.01.

10-isobutyryl-10-DAB. mp 143° C.; [α]_(Hg) −62.6° (CHCl₃, c=0.075); ¹HNMR (CDCl₃, 500 MHz): δ 8.12 (2H, d, J 7.3 Hz), 7.62 (1H, m), 7.51-7.48(2H, m), 6.33 (1H, s), 5.65 (1H, d, J 7.3 Hz), 5.00 (1H, d, J 7.9 Hz),4.91. (1H, m), 4.48 (1H, ddd, J 4.3, 6.7, 11.0 Hz), 4.31 (1H, d, J 8.6Hz), 4.18 (1H, d, J 8.6 Hz), 3.91 (1H, d, J 7.3 Hz), 2.74 (1H, pent, J6.7 Hz), 2.57 (1H, m), 2.51 (1H, d, J 4.3 Hz), 2.31 (1H, m), 2.28 (3H,s), 2.06 (3H, s), 2.01 (1H, d, J 5.5 Hz), 1.90 (1H, ddd, J 2.3, 11.0,14.6 Hz), 1.68 (3H, s), 1.60 (1H, s)i 1.51 (3H, s), 1.33 (3H, d, J 6.7Hz), 1.26 (3H, d, J 6.7 Hz), 1.13 (3H, s) and 1.12 (3H, s); ¹³C NMR (100MHz, CDCl₃) δ 204.1, 177.2, 170.6, 167.1, 146.2, 133.7, 132.1, 130.1,129.4, 128.6, 95.5, 84.5, 80.9, 79.1, 76.5, 75.8, 74.9, 72.3, 68.0,58.8, 46.2, 42.7, 38.7, 35.6, 34.1, 27.0, 22.6, 20.9, 19.2, 18.7, 15.5and 9.4; Anal. Calcd. for C₃₃H₄₂O₁₁.0.5H₂O: C, 64.48; H, 6.89 Found: C,63.05; H, 6.70.

10-benzoyl-10-DAB. ¹H NMR (CDCl₃, 500 MHz): δ 8.15-8.11 (4H, m),7.64-7.6 (2H, m), 7.52-7.48 (4H, m), 6.62 (1H, s), 5.7 (1H, d, J 7.1Hz), 5.02 (1H, d, J 7.7 Hz), 4.94 (1H, m), 4.57 (1H, ddd, J 4.4, 7.1,11.0 Hz), 4.33 (1H, d, J 8.2 Hz), 4.20 (1H, d, J 8.3 Hz), 3.99 (1H, d, J6.6 Hz), 2.62 (1H, ddd, J 6.6, 9.3, 14.8), 2.55 (1H, d, J 4.4 Hz), 2.35(2H, m), 2.30 (3H, s), 2.13 (3H, d, J 1.1 Hz), 2.03 (1H, d, J 4.9 Hz),1.91 (1H, ddd, J 2.2, 11.0, 13.2 Hz), 1.71 (3H, s), 1.65 (1H, s), 1.25(3H, s) and 1.21 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 204.0, 170.7,167.1, 166.5, 146.5, 133.7, 133.6, 132.0, 130.1, 129.9, 129.4, 129.3,128.7, 128.5, 84.5, 80.9, 79.1, 76.5, 75.0, 72.4, 68.1, 58.8, 46.3,42.8, 38.7, 35.8, 29.7, 27.2, 22.6, 21.2, 15.6 and 9.5; Anal. Calcd. forC₃₅H₄₀O₁₁: C, 66.66; H. 6.22 Found C, 66.46; H, 6.19.

10-trans crotonyl-10-DAB. ¹H NMR (CDCl₃, 500 MHz): δ 8.13 (2H, d, J 7.1Hz), 7.62 (1H, m), 7.51-7.48 (2H, m), 7.11 (1H, m), 6.42 (1H, s), 6.02(1H, dq, J 1.7, 15.4 Hz), 5.66 (1H, d, J 7.1 Hz), 4.99 (1H, dd, J 2.0,9.6 Hz), 4.91 (1H, t, J 7.6 Hz), 4.50 (1H, dd, J 7.1, 10.8 Hz), 4.31(1H, d, J 8.3 Hz), 4.19 (1H, d, J 8.3 Hz), 3.93 (1H, d, J 7.1 Hz),2.61-2.55 (2H, m), 2.33-2.31 (2H, m), 2.28 (3H, s), 2.07 (3H, d, J 1.5Hz), 1.95 (3H, dd, J 1.6, 6.8 Hz), 1.89 (1H, ddd, J 2.3, 11.0, 13.4 Hz),1.68 (3H, s), 1.15 (3H, s) and 1.14 (3H, S); ¹³C NMR (75 MHz, CDCl₃) δ212.4, 181.0, 170.8, 167.3, 166.5, 146.4, 133.8, 132.3, 130.2, 129.5,128.7, 121.9, 116.0, 84.7, 84.6, 80.9, 79.2, 77.2, 75.9, 75.1, 72.4,68.1, 58.8, 46.1, 42.7, 38.6, 35.6, 27.0, 20.9, 18.0, 15.4 and 9.3;Anal. Calcd. for C₃₃H₄₀O₁₁: C, 64.69; H, 6.58 Found C, 63.93; H, 6.61.

10-cyclopropanoyl-10-DAB. ¹H (CDCl₃, 500 MHz): δ 8.12 (2H, d, J 7.3 Hz),7.62 (1H, t, J 7.5 Hz), 7.49 (2H, t, J 7.7 Hz), 6.35 (1H, s), 5.65 (1H,d, J 7.0 Hz), 4.99 (1H, app-d, J 8.2 Hz), 4.91 (1H, m), 4.46 (1H, ddd, J4.1, 6.8, 10.8 Hz), 4.31 (1H, d, J 8.1 Hz), 4.18 (1H, d, J 8.1 Hz), 3.90(1H, d, J 7.0 Hz), 2.56 (1H, m), 2.51 (1H, d, J 4.1 Hz), 2.31 (2H, m),2.07 (3H, d, J 1.0 Hz), 2.00 (1H, d, J 4.9 Hz), 1.87 (1H, ddd, J 2.1,10.8, 14.6 Hz), 1.79 (1H, ddd, J 3.4, 7.9, 12.4 Hz), 1.68 (3H, s), 1.60(1H, s), 1.16-1.14 (2H, m), 1.13 (6H, s) and 1.01-0.97 (2H, m); ¹³C NMR(100 MHz, CDCl₃) δ 204.3, 175.2, 170.6, 167.1, 146.4, 133.7, 132.0,130.1, 129.4, 128.6, 84.5, 80.9, 79.1, 76.5, 76.0, 74.9, 72.4, 68.0,58.8, 46.2, 42.7, 38.6, 35.6, 34.0, 27.0, 25.6, 24.9, 22.6, 21.0, 15.6,13.1, 9.4 and 9.1; Anal. Calcd. for C₃₃H₄₀O₁₁: C, 64.69; H, 6.58 Found:C, 64.47; H, 6.66.

10-Ethoxycarbonyl-10-DAB. mp 214-215° C.; [α]_(Hg) −81° (CHCl₃, c=0.35);¹H NMR (500 MHz, CDCl₃) δ 1.13(s, 3 H, Me17), 1.14(s, 3 H, Me16),1.38(t, J=7.1 Hz, 3 H, CH₃CH₂), 1.59(s, 1 H, 1-OH), 1.70(s, 3 H, Me19),1.88(ddd, J=14.6, 10.5, 2.1 Hz, 1 H, H6b), 2.00(d, J=5.0 Hz, 1 H,13-OH), 2.10(d, J=1.4 Hz, 3 H, Me18), 2.28(s, 3 H, 4-Ac), 2.30(m, 2 H,H14a, H14b), 2.46(d, J=4.2 Hz, 1 H, 7-OH), 2.57(ddd, J=14.6, 9.6, 6.7Hz, 1 H, H6a), 3.88(d, J=6.9 Hz, 1 H, H3), 4.18(d, J=8.2 Hz, 1 H, H20b),4.31(d, J=8.2 Hz, 1 H, H20a), 4.23-4.33(m, 2 H, CH₃CH₂); 4.44(ddd,J=10.5, 6.7, 4.2 Hz, 1 H, H7), 4.90(m, 1 H, H13), 4.98(dd, J=9.6, 2.1Hz, 1 H, H5), 5.65(d, J=6.9 Hz, 1 H, H2), 6.17 (s, 1 H, H10), 7.48(dd,J=8.2, 7.3 Hz, 2 H, benzoate, m), 7.60(tt, J=7.3, 1.4 Hz, 1 H, benzoate,p), 8.11(d, J=8.2, 1.4 Hz, 2 H, benzoate, o) ppm; ¹³C NMR (75 MHz,CDCl₃) δ 9.2, 14.0, 15.5, 20.8, 22.4, 26.7, 35.4, 38.5, 42.4, 46.0,58.6, 65.0, 67.7, 72.2, 74.9, 76.4, 78.7, 79.0, 80.6, 84.4, 128.7,129.4, 130.1, 131.5, 133.7, 147.5, 155.4, 167.1, 170.8, 204.7 ppm.

10-Methoxycarbonyl-10-DAB. mp 218-219° C.; [α]_(Hg) −83° (CHCl₃,c=0.58); ¹H NMR (500 MHz, CDCl₃) δ 1.12 (s, 3 H, Me17), 1.13(s, 3 H,Me16), 1.59(s, 1 H, 1-OH), 1.70(s, 3 H, Me19), 1.88(ddd, J=14.7, 10.8,1.8 Hz, 1 H. H6b), 2.00(d, J=5.0 Hz, 1 H, 13-OH), 2.10(d, J=1.4 Hz, 3 H,Me18), 2.28(s, 3 H, 4-Ac), 2.30(m, 2 H, H14a, H14b), 2.40(d, J=4.1 Hz, 1H, 7-OH), 2.57(ddd, J=14.7, 9.7, 6.6 Hz, 1 H, H6a), 3.87(d, J=6.9 Hz, 1H, H3), 3.88(s, 3 H, MeOC(O)), 4.18(d, J=8.4 Hz, 1 H, H20b), 4.31(d,J=8.4 Hz, 1 H, H20a), 4.44(ddd, J=10.8, 6.6, 4.1 Hz, 1 H. H7), 4.90(m, 1H, H13), 4.98(dd, J=9.7, 1.8 Hz, 1 H, H5), 5.65(d, J=6.9 Hz, 1 H, H2),6.17(s, 1 H, H10), 7.48(t, J=8.2, 7.3 Hz, 2 H, benzoate, m), 7.61(tt,J=7.3, 1.4 Hz, 1 H, benzoate, p), 8.11(d, J=8.2, 1.4 Hz, 2 H, benzoate,o) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 9.2, 15.5, 20.7, 22.4, 26.7, 35.5,38.5, 42.4, 46.0, 55.4, 58.6, 65.0, 67.7, 72.1, 74.8, 76.4, 78.9, 79.0,80.6, 84.4, 128.7, 129.4, 130.1, 131.4, 133.7, 147.5, 155.9, 167.1,170.8, 204.6 ppm.

10-tBoc-10-DAB. mp 193-194° C.; [α]_(Hg) −82° (CHCl₃; c=0.33); ¹H NMR(500 MHz, CDCl₃) δ 1.13(s, 6 H, Me17, Me16), 1.48(s, 9 H, tBuO), 1.58(s,1 H, 1-OH), 1.69(s, 3 H, Me19), 1.88(ddd, J=14.9, 11.0, 2.2 Hz, 1 H,H6b), 1.99(d, J=5.0 Hz, 1 H, 13-OH), 2.08(d, J=1.4 Hz, 3 H, Me18),2.28(s, 3 H, 4-Ac), 2.30(m, 2 H, H14a, H14b), 2.56(ddd, J=14.9, 9.6, 6.9Hz, 1 H, H6a), 2.68(d, J=3.6 Hz, 1 H, 7-OH), 3.88(d, J=6.9 Hz, 1 H, H3),4.19(d, J=8.2 Hz, 1 H, H20b), 4.31(d, J=8.2 Hz, 1 H, H20a), 4.46(ddd,J=11.0, 6.9, 3.6 Hz, 1 H, H7), 4.90(m, 1 H, H13), 4.99(dd, J=9.6, 2.2Hz, 1 H, H5), 5.64(d, J=6.9 Hz, 1 H, H2), 6.11(s, 1 H, H10), 7.48(t,J=7.8 Hz, 2 H, benzoate, m), 7.60(tt, J=7.8, 1.3 Hz, 1 H, benzoate, p),8.11(dd, J=7.8, 1.3 Hz, 2 H, benzoate, 0) ppm; ¹³C NMR (75 MHz, CDCl₃) δ9.2, 15.6, 20.9, 22.4, 26.8, 27.5, 35.3, 38.5, 42.5, 45.9, 58.7, 67.9,72.3, 74.7, 76.4, 78.0, 79.2, 80.8, 83.8, 84.5, 128.7, 129.4, 130.1,131.8, 133.7, 147.3, 154.0, 167.2, 170.8, 205.0 ppm.

D. Selective Carbamoylation of a C(10) Hydroxyl Group:

General procedure for the Selective Carbamoylation of the C-10 Hydroxylgroup of 10-DAB: A solution of 0.061 mmol (1.1 mol equiv) of theisocyanate in 2 mL of THF was added, under nitrogen, to a mixture of10-DAB (30 mg, 0.055 mmol) and CuCl (5.5 mg, 0.055 mmol) at 0° C. Themixture was stirred for the time indicated in Table 2. After this timethe reaction was warmed to 25° C. and stirring was continued for thetime indicated in Table 2. The reaction was quenched by the addition ofsaturated aqueous ammonium chloride solution, and the mixture wasextracted three times with EtOAc. The combined organic layers werewashed with saturated aqueous NaHCO₃ solution, dried over sodiumsulfate, and the solvent was evaporated to yield a white solid. Theproduct was purified by flash column chromatography using 2:1EtOAc/hexane as the eluent. TABLE 2 Carbamoylation of 10-DAB

Entry R (eq) Temp (° C.) Time (hr) Yield (%) 1 Et (1.1) 0 7.5 88 rt 0.52 allyl (1.1) 0 6 88 rt 0.5 3 Bu (1.1) 0 6.5 87 rt 0.5 4 Ph (1.1) rt 394

10-ethylcarbamoyl-0-DAB. mp 241-243° C.; [α]_(Hg) −92.0° (CHCl₃, c=0.5);¹H NMR (400 MHz, CDCl₃) δ 8.13 (2H, d, J 7.1 Hz), 7.63 (1H, m),7.52-7.48 (2H, m), 6.27 (1H, s), 5.63 (1H, d, J 6.9 Hz), 5.01 (1H, dd, J1.9, 9.6 Hz), 4.97 (1H, m), 4.91 (1H, m), 4.50 (1H, ddd, J 3.7, 6.5,10.5 Hz), 4.31 (1H, d, J 8.3 Hz), 4.17 (1H, d, J 8.3 Hz), 3.88 (1H, d, J7.0 Hz), 3.32-3.25 (2H, m), 3.10 (1H, d, J 3.2 Hz), 2.56 (1H, ddd, J6.8, 9.8, 14.8 Hz), 2.31 (1H, m) 2.29 (3H, s), 2.09 (3H, s), 1.88 (1H,ddd, J 2.2, 11.0, 13.3 Hz), 1.67 (3H, s), 1.60 (1H, s), 1.19 (3H, t, J7.2 Hz) and 1.10 (6H, s); Anal. Calcd. for C₃₂H₄₀NO₁₁: C, 62.43; H, 6.71Found: C, 61.90; H, 6.77.

10-butylcarbamoyl-10-DAB. [α]_(Hg) −89.6° (CHCl₃, c=0.25); ¹H NMR (500MHz, CDCl₃) δ 8.12 (2H, d, J 7.3 Hz), 7.61 (1H, m), 7.51-7.45 (2H, m),6.27 (1H, s), 5.64 (1H, d, J 6.7 Hz), 5.00 (1H, d, J 8.0 Hz), 4.91 (1H,m), 4.49 (1H, m), 4.31 (1H, d, J 8.5 Hz), 4.19 (1H, d, J 8.5 Hz), 3.89(1H, d, J 6.7 Hz), 3.25-3.23 (2H, m), 3.04 (1H, m), 2.56 (1H, ddd, J6.7, 9.7, 14.7 Hz), 2.30 (1H, d, J 7.9 Hz), 2.28 (3H. s), 2.09 (3H, s),1.99 (1H, d, J 4.9 Hz), 1.88 (1H, ddd, J 2.5, 11.0, 13.4 Hz), 1.68 (3H,s), 1.59 (1H, s), 1.55 (2H, b), 1.42-1.37 (2H, m), 1.11 (6H, s) and 0.95(3H, t, J 7.6 Hz); Anal. Calcd. for C₃₄H₄₄NO₁₁: C, 63.44; H, 7.05 Found:C, 62.64; H, 7.01.

10-phenylcarbamoyl-10-DAB. mp 178-180° C.; [α]_(Hg) −93.0° (CHCl₃,c=0.5); ¹H NMR(400 Hz, CDCl₃) δ 8.13 (2H, d, J 6.9 Hz), 7.63 (1H, t, J7.4 Hz), 7.51 (2H, t, J 7.6 Hz), 7.42 (1H, d, J 7.8 Hz), 7.36-7.32 (2H,m), 7.12 (1H, t, J 7.4 Hz), 6.87 (1H, b), 6.38 (1H, s), 5.66 (1H, d, J7.0 Hz), 5.02 (1H, app d, J 7.8 Hz), 5.93 (1H, m), 4.52 (1H, ddd, J 3.8,6.5, 10.5 Hz), 4.33 (1H, d, J 8.3 Hz), 4.18 (1H, d, J 8.3 Hz), 3.91 (1H,d, J 7.0 Hz), 2.83 (1H, d, J 4.0 Hz), 2.59 (1H, ddd, J 6.5, 9.4, 14.5Hz), 2.33 (1H, m), 2.29 (3H, s), 2.12 (3H, d, J 1.4 Hz), 2.04 (1H, d, J5.1 Hz), 1.89 (1H, ddd, J 2.2, 11.0, 14.4 Hz), 1.69 (3H, s), 1.62 (1H,s), 1.15 (3H, s) and 1.13 (3H, s).

10-allylcarbamoyl-10-DAB. mp 165-170° C.; [α]_(Hg) −80.0° (CHCl₃,c=0.25); ¹H NMR(500 MHz, CDCl₃) δ 8.12 (2H, d, J 7.3 Hz), 7.62 (1H, m),7.51-7.48 (2H, m), 6.27 (1H, s) 5.89 (1H, m), 5.62 (1H, d, J 6.7 Hz),5.31 (1H, s) 5.19 (1H, d, J 9.8 Hz), 5.08 (1H, m), 5.00 (1H, d, J 7.9Hz), 4.90 (1H, m), 4.49 (1H, ddd, J, 3.7, 6.1, 10.4 Hz), 4.31 (1H, d, J8.5 Hz), 4.17 (1H, d, J 8.5 Hz), 3.88-3.86 (2H, m), 3.03 (1H, d, J 3.7Hz), 2.55 (1H, ddd, J 6.7, 9.8, 15.9 Hz), 2.30 (1H, m), 2.29 (3H, s),2.08 (3H, s), 2.06 (1H, app d, J 4.9 Hz), 1.87 (1H, ddd, J 1.8, 11.0,14.0 Hz), 1.67 (3H, s), 1.58 (1H, s) and 1.09 (6H, s); Anal. Calcd. forC₃₃H₄₀NO₁₁: C, 63.15; H, 6.58 Found: C, 61.73; H, 6.45.

E. Selective Silylation of a C(10) Hydroxyl Group:

10-TMS-10-DAB. To a solution of 10-DAB (100 mg, 0.18 mmol) in THF (10mL) at 0° C. was slowly added N, O-bis(trimethylsilyl)trifluoroacetamide(1.0 mL, 3.7 mmol, 20 equiv) under N₂. The reaction mixture was stirredat 0° C. for 5 h. EtOAc (20 mL) was added, and the solution was filteredthrough a short column of silica gel. The silica gel was washed withEtOAc (100 mL), and the solution was concentrated under reducedpressure. The residue was purified by flash column chromatography usingEtOAc: hexanes (1:1) as the eluent and dried in vacuo overnight to give10-TMS-10-DAB as a white solid: yield, 103 mg (91%). mp 189-191° C.;[α]_(Hg) −70° (CHCl₃, c=−0.55); ¹H NMR (400 MHz, CDCl₃) δ 0.18 (s, 9 H,Me₃Si) 1.06(s, 3 H, Me17), 1.16(s, 3 H, Me16), 1.31(d, J=8.6 Hz, 1 H,7-OH), 1.56(s, 1 H, 1-OH), 1.68(s, 3 H, Me19), 1.79(ddd, J=14.4, 11.1,2.1 Hz, 1 H, H6b), 1.97(d, J=4.9 Hz, 1 H, 13-OH), 2.03(d, J=1.3 Hz, 3 H,Me18), 2.27(m, 2 H, H14a, H14b), 2.28(s, 3 H, 4-Ac), 2.58(ddd, J=14.4,9.6, 7.5 Hz, 1 H, H6a), 4.01(d, J=7.2 Hz, 1 H, H3), 4.16(d, J=8.2 Hz, 1H, H20b), 4.25(ddd, J=11.1, 8.6, 7.5 Hz, 1 H, H7), 4.30(d, J=8.2 Hz, 1H, H20a), 4.84(m, 1 H, H13), 4.97(dd, J=9.6, 2.1 Hz, 1 H, H5), 5.27(s, 1H, H10), 5.64(d, J=7.2 Hz, 1 H, H2), 7.47(dd, J=8.2, 7.5 Hz, 2 H,benzoate, m), 7.60(tt, J=7.5, 1.2 Hz, 1 H, benzoate, p), 8.11(dd, J=8.2,1.2 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 0.2(Me₃S),9.7(Me(19)), 14.4(Me(18)), 19.6(4-Ac), 22.4, 26.6(Me16, Me17),37.1(C(6)), 38.6(C(14)), 42.6(C(15)), 47.2(C(3)), 57.8(C(8)),68.0(C(13)), 72.0, 75.1, 76.1, 76.8(C(7), C(2), C(10), C(20)),78.9(C(1)), 81.2(C(4)), 84.3(C(5)), 128.8, 130.3, 133.7(benzoate),137.0(C(11)), 139.0(C(12)), 167.4(benzoate), 171.0(4-Ac),209.5(C(9))ppm. Anal. Calcd for C₃₂H₄₄O₁₀Si. 1/2H₂O: C, 61.42; H, 7.25.Found: C, 61.61; H, 7.12.

10-TES-10-DAB. To a solution of 10-DAB (85 mg, 0.16 mmol) in THF (3 mL)at 0° C. was slowly-added N, O-bis(triethylsilyl)trifluoroacetamide (484mL, 1.56 mmol, 10 equiv), and a catalytic amount of LiHMDS/THF solution(1 M, 5 mL, 0.005 mmol), respectively, under N₂. The reaction mixturewas stirred at 0° C. for 5 min. EtOAc (10 mL) was added, and thesolution was filtered through a short column of silica gel. The silicagel was washed with EtOAc (100 mL), and the solution was concentratedunder reduced pressure. The residue was purified by flash columnchromatography using EtOAc: hexanes (1:2) as the eluent and dried invacuo overnight to give the 10-TES-10-DAB as a white solid: yield, 98 mg(95%). mp 234-235° C. dec; [α]_(Hg) −69° (CHCl₃, c=0.95); IR 3690, 2958,1714, 1602 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.68(m, 6 H, (CH₃CH₂)₃Si),1.00(t, J=7.9, 9 H, (CH₃CH₂)₃Si), 1.08 (s, 3 H, Me17), 1.19(s, 3 H,Me16), 1.29(d, J=8.4 Hz, 1 H, 7-OH), 1.55(s, 1 H, 1-OH), 1.69(s, 3 H,Me19), 1.79(ddd, J=14.4, 11.0, 2.0 Hz, 1 H, H6b), 1.92(d, J=5.0 Hz, 1 H,13-OH), 2.03(d, J=1.0 Hz, 3 H, Me18), 2.27(s, 3 H, 4-Ac), 2.29(m, 2 H,H14a, H14b), 2.59(ddd, J=14.4, 9.5, 6.7 Hz, 1 H, H6a), 4.02(d, J=7.2 Hz,1 H, H3), 4.18(d, J=8.5 Hz, 1 H, H20b), 4.23(ddd, J=11.0, 8.4, 6.7 Hz, 1H, H7), 4.30(d, J=8.5 Hz, 1 H, H20a), 4.86(m, 1 H, H13), 4.97(dd, J=9.5,2.0 Hz, 1 H, H5), 5.28(s, 1 H, H10), 5.66(d, J=7.2 Hz, 1 H, H2),7.47(dd, J=7.9, 7.9 Hz, 2 H, benzoate, m), 7.59(tt, J=7.9, 1.0 Hz, 1 H,benzoate, p), 8.11(dd, J=7.9, 1.0 Hz, 2 H, benzoate, o)ppm. ¹³C NMR (75MHz, CDCl₃) δ 4.9, 6.5(TES), 9.7(Me(19)), 14.3(Me(18)), 19.6(4-Ac),22.4, 26.6(Me16, Me17), 37.1 (C(6)), 38.6 (C(14)), 42.6 (C(15)), 47.3(C(3)) 57.9(C(8)), 67.9(C(13)), 71.9, 75.1, 76.1, 76.7(C(7), C(2),C(10), C(20)), 78.9 (C(1)), 81.2 (C(4)), 84.3 (C(5)), 128.7, 129.9,130.3, 133.7(benzoate), 137.0(C(11)), 138.8(C(12)), 167.4(benzoate),171.0(4-Ac), 209.5(C(9)) ppm. Anal. Calcd for C₃₅H₅₀O₁₀Si H₂O: C, 62.11;H, 7.74. Found: C, 62.45; H, 7.74.

EXAMPLE 2

General Procedure for the Preparation of 7-silyl-10-TES-10-DAB. To asolution of 7-triethylsilyl-10-DAB, 7-t-butyldimethylsilyl-10-DAB, or7-dimethylisopropylsilyl-10-DAB in THF at 0° C. was slowly added N,0-bis(tri-ethylsilyl)trifluoroacetamide (5 equiv), and a catalyticamount of LiHMDS/THF solution (5 mol %), respectively, under N₂. Thereaction mixture was stirred at 0° C. for 15 min. EtOAc (10 mL) wasadded, and the solution was filtered through a short column of silicagel. The silica gel was washed with EtOAc (100 mL), and the solution wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using EtOAc: hexanes (1:2) as the eluent and driedin vacuo overnight to give, respectively, 7,10-bis(triethylsilyl)-10-DAB(95% yield), 7-t-butyldimethylsilyl-10-triethylsilyl-10-DAB (98% yield),or 7-dimethyliso-propylsilyl-10-triethylsilyl-10-DAB (94% yield).

7-Dimethylphenylsilyl-10-TBS-10-DAB. To a solution of7-dimethylphenylsilyl-10-DAB (35 mg, 0.052 mmol) in THF (2 mL) at 0° C.was added N,O-bis(t-butyldimethylsilyl)trifluoroacetamide (337 μL, 1.09mmol, 20 equiv), and a catalytic amount of LiHMDS/THF solution (1 M, 6μL, 0.006 mmol), respectively, under N₂. The reaction mixture wasstirred at 0° C. for 4 h, then warmed to room temperature for anadditional 4 h. EtOAc (10 mL) was added, and the solution was filteredthrough a short column of silica gel. The silica gel was washed withEtOAc (100 mL), and the solution was concentrated under reducedpressure. The residue was purified by flash column chromatography usingEtOAc: hexanes (1:2) as the eluent and dried in vacuo overnight to give39 mg (92% yield) of7-dimethylphenylsilyl-10-t-butyldimetylsilyl-10-DAB.

EXAMPLE 3 Selective Silylation of a C(7) Hydroxyl Group

7-TBS-10-DAB. To a mixture of 10-DAB (38 mg, 0.070 mmol), imidazole (190mg, 2.79 mmol, 40 equiv), and tert-butyldimethylsilyl chloride (210 mg,1.40 mmol, 20 equiv) was added DMF (0.1 mL) at room temperature underN₂. The reaction mixture was vigorously stirred at room temperature for24 h. EtOAc (20 mL) was added, and the solution was filtered through ashort column of silica gel. The silica gel was washed with EtOAc (200mL), and the solution was concentrated under reduced pressure. Theresidue was purified by flash column chromatography using 10%EtOAc-CH₂Cl₂ as the eluent and dried in vacuo overnight to give7-TBS-10-DAB as a white solid: yield, 41 mg (90%). mp 222-223° C.;[α]_(Hg) −51° (CHCl₃, c=0.36); ¹H NMR (400 MHz, CDCl₃) δ 0.05, 0.06(2 s,6 H, Me₂Si), 0.83(s, 9 H, Me₃C), 1.09(s, 6 H, Me16, Me17), 1.57(s, 1 H,1-OH), 1.75(s, 3 H, Me19), 1.87(ddd, J=14.4, 10.6, 2.0 Hz, 1 H, H6b),2.01(d, J=5.0, Hz, 1 H, 13-OH), 2.09(d, J=1.3, 3 H, Me18), 2.28(m, 2 H,H14a, H14b), 2.29(s, 3 H, 4-Ac), 2.46(ddd, J=14.4, 9.6, 6.7 Hz, 1 H,H6a), 3.96(d, J=6.9 Hz, 1 H, H3), 4.16(d, J=8.3 Hz, 1 H, H20b), 4.24(d,J=2.2 Hz, 1 H, 10-OH), 4.31(d, J=8.3 Hz, 1 H, H20a), 4.38(dd, J=10.6,6.7 Hz, 1 H, H7), 4.88(m, 1 H, H13), 4.96(dd, J=9.6, 2.0 Hz, 1 H, H5),5.15(d, J=2.0 Hz, 1 H, H10), 5.60(d, J=6.9 Hz, 1 H, H2), 7.47(dd,.J=8.1, 7.5 Hz, 2 H, benzoate, m), 7.60(tt, J=7.5, 1.3 Hz, 1 H, benzoate,p), 8.10(d, J=8.1, 1.3 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz,CDCl₃) δ −5.8, −3.8(Me₂Si), 9.7(Me(19)), 14.8(Me(18)) 17.6(Me₃C),19.3(4-Ac), 22.4, 26.7(Me16, Me17), 25.4 (Me₃C), 37.4(C(6)),38.7(C(14)), 42.7(C(15)), 47.0(C(3)), 58.0(C(8)), 68.0(C(13)), 73.1,74.7, 75.0(C(7), C(2), C(10), C(20)), 78.9(C(1)), 80.9(C(4)),84.3(C(5)), 128.8, 129.8, 130.3, 133.8(benzoate), 135.7(C(11)),141.9(C(12)), 167.4(benzoate), 171.2(4-Ac), 210.8(C(9))ppm. Anal. Calcdfor C₃₅H₁₀O₁₀Si: C, 63.80; H, 7.65. Found: C, 63.72; H, 7.70.

7-Dimethylphenylsilyl-10-DAB. To a THF (3 mL) solution of 10-DAB (54 mg,0.099 mmol) at −20° C. was added pyridine (0.6 mL), dimethylphenylsilylchloride (250 mL, 1.49 mmol, 15 equiv) under N₂. The reaction mixturewas stirred at −20° C. for 2 h. EtOAc (10 mL) and saturated NaHCO₃aqueous solution (0.5 mL) was added, and the solution was quicklyfiltered through a short column of silica gel. The silica gel was washedwith EtOAc (100 mL), and the solution was concentrated under reducedpressure. The residue was purified by flash column chromatography usingEtOAc: CH₂Cl₂ (1:10) as the eluent and dried overnight in vacuo to give7-dimethylphenyl-silyl-10-DAB as a white solid: yield, 62 mg (92%). mp219-220° C.; [α]_(Hg) −28° (CHCl₃, c=0.27); ¹H NMR (400 MHz, CDCl₃) δ0.35, 0.37-(2 s, 6 H, Me₂Si), 1.05 (s, 3 H, Me17) 1.06(s, 3 H, Me16),1.54(s, 1 H, 1-OH), 1.73(d, J=1.1, 3 H, Me18), 1.76(s, 3 H, Me19),1.90(ddd, J=14.4, 10.6, 2.1 Hz, 1 H, H6b), 1.93(d, J=5.0 Hz, 1 H,13-OH), 2.23(m, 2 H, H14a, H14b), 2.25(s, 3 H, 4-Ac), 2.43(ddd, J=14.4,9.6, 6.8 Hz, 1 H, H6a), 3.86(d, J=7.0 Hz, 1 H, H3), 4.10(d, J=2.1 Hz, 1H, 10-OH), 4.16(d, J=8.3 Hz, 1 H, H20b), 4.28(d, J=8.3 Hz, 1 H, H20a),4.31(dd, J=10.6, 6.8 Hz, 1 H, H7), 4.81(m, 1 H, H13), 4.84(d, J=2.1 Hz,1 H, H10), 4.90(dd, J=9.6, 2.1 Hz, 1 H, H5), 5.59(d, J=7.0 Hz, 1 H, H2),7.41, 7.53(2 m, 5 H, C₆H₅), 7.46(dd, J=8.0, 7.5 Hz, 2 H, benzoate, m),7.55(tt, J=7.5, 1.2 Hz, 1 H, benzoate, p), 8.09(d, J=8.0, 1.2 Hz, 2 H,-benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ −1.8, −1.1(Me₂Si),9.8(Me(19)), 14.4(Me(18)), 19.4(4-Ac), 22.3, 26.7(Me16, Me17),37.2(C(6)), 38.6(C(14)), 42.6(C(15)), 46.7(C(3)), 58.0(C(8)),68.0(C(13)), 73.2, 74.7, 75.0(C(7), C(2), C(10), C(20)), 78.8(C(1)),80.8(C(4)), 84.3(C(5)), 128.3, 128.8, 129.8, 130.2, 130.3, 133.65,133.74(PhSi, benzoate), 135.4(C(11)), 142.1(C(12)), 167.4(benzoate),171.0(4-Ac), 210.9(C(9))ppm. Anal. Calcd for C₃₇H₄₆O₁₀Si. 1/2H₂O: C,64.61; H, 6.89. Found: C, 64.72; H, 6.81.

7-Dimethylisopropylsilyl-10-DAB. To a solution of 10-DAB (97 mg, 0.18mmol) in pyridine (1 mL) at −10° C. was added dimethylisopropylsilylchloride (580 mL, 3.57 mmol, 20 equiv) under N₂. The reaction mixturewas stirred at −10° C. for 3 h. EtOAc (10 mL) was added, and thesolution was quickly filtered through a short column of silica gel. Thesilica gel was washed with EtOAc (150 mL), and the solution wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using EtOAc: hexanes (1:2) as the eluent to give7-dimethylisopropyl-10-DAB as a white solid: yield, 107 mg (93%). mp229-230° C.; [α]_(Hg) −56° (CHCl₃, c=0.62); ¹H NMR (400 MHz, CDCl₃) δ0.05, 0.06(2 s, 6 H, Me₂Si) 0.70(m, 1 H, CHSi), 0.90, 0.92(2 dd, J=7.4,1.7, 6 H, Me₂CH), 1.09(s, 6 H, Me16, Me17), 1.56(s, 1 H, 1-OH), 1.74(s,3 H, Me19), 1.89(ddd, J=14.4, 10.6, 2.1 Hz, 1 H, H6b), 1.99(d, J=5.0 Hz,1 H, 13-OH), 2.09(d, J=1.4, 3 H, Me18), 2.28(d, J=7.9, 2 H, H14a, H14b),2.29(s, 3 H, 4-Ac), 2.44(ddd, J=14.4, 9.7, 6.7 Hz, 1 H, H6a), 3.96(d,J=7.3 Hz, 1 H, H3), 4.17(d, J=8.3 Hz, 1 H, H20b), 4.24(d, J=2.2 Hz, 1 H,10-OH), 4.31(d, J=8.3 Hz, 1 H, H20a), 4.38(dd, J=10.6, 6.7 Hz, 1 H, H7),4.85(m, 1 H, H13), 4.95(dd, J=9.7, 2.1 Hz, 1 H, H5), 5.15(d, J=2.2 Hz, 1H, H10), 5.61(d, J=7.3 Hz, 1 H, H2), 7.47(dd, J=8.2, 7.5 Hz, 2 H,benzoate, m), 7.60(tt, J=7.5, 1.4 Hz, 1 H, benzoate, p), 8.10(d, J=8.2,1.4 Hz, 2 H, benzoate, o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ −4.6, −3.3(Me₂Si), 9.7(Me(19)), 14.8, 14.9(CHSi, Me(18)), 16.4, 16.5(Me₂CH),19.4(4-Ac), 22.4, 26.7(Me16, Me17), 37.3(C(6)), 38.7(C(14)),42.7(C(15)), 47.0(C(3)), 58.0(C(8)), 68.0(C(13)), 73.1, 74.7, 75.0(C(7),C(2), C(10), C(20)), 78.9(C(l)), 80.9(C(4)), 84.3(C(5)), 128.8, 129.8,130.3, 133.7(benzoate), 135.7(C(11)), 142.0(C(12)), 167.4(benzoate),171.1(4-Ac), 210.8(C(9)) ppm. Anal. Calcd for C₃₄H₄₈O₁₀Si. H₂O: C,61.61; H, 7.60. Found: C, 61.30; H, 7.35.

7-Tribenzylsilyl-10-DAB. To a mixture of 10-DAB (62 mg, 0.11 mmol),imidazole (280 mg, 4.11 mmol, 36 equiv) and tribenzylsilyl chloride (364mg, 1.14 mmol, 10 equiv) was added DMF (0.4 mL) under N₂. The reactionmixture was stirred at room temperature for 3 h. EtOAc (30 mL) wasadded, and the solution was filtered through a short column of silicagel. The silica gel was washed with EtOAc (150 mL), and the solution wasconcentrated under reduced pressure. The residue was purified twice byflash column chromatography, first time using EtOAc: hexanes (1:2) asthe eluent, second time using EtOAc: CH₂Cl₂ as the eluent, and driedovernight in vacuo to give the 7-tribenzylsilyl-10-DAB as a white solid:yield, 88 mg (91%). mp 161-163° C.; IR 3690, 2928, 2890, 1712, 1600cm⁻¹; [α]_(Hg) −46° (CHCl₃, c=0.46); ¹H NMR (400 MHz, CDCl₃) δ 1.10(s, 3H, Me17, Me16), 1.56(s, 1 H, 1-OH), 1.71(ddd, J=14.2, 10.9, 2.0 Hz, 1 H,H6b), 1.74(s, 3 H, Me19), 2.00(d, J=5.1 Hz, 1 H, 13-OH), 2.07(ddd,J=14.2, 9.6, 6.6 Hz, 1 H, H6a), 2.10(d, J=1.2, 3 H, Me18), 2.12(s, 6 H,(PhCH₂)₃Si), 2.27(d, J=7.5 Hz, 2 H, H14a, H14b), 2.27(s, 3 H, 4-Ac),3.99(d, J=7.0 Hz, 1 H, H3), 4.16(d, J=8.5 Hz, 1 H, H20b), 4.18(d, J=2.2Hz, 1 H, 10-OH), 4.28(d, J=8.5 Hz, 1 H, H20a), 4.58(dd, J=10.9, 6.6 Hz,1 H, H7), 4.81(dd, J=9.6, 2.0 Hz, 1 H, H5), 4.89(m, 1 H, H13), 5.21(d,J=2.2 Hz, 1 H, H10), 5.61(d, J=7.0 Hz, 1 H, H2), 6.93, 7.09, 7.20(3 m,15 H, (PhCH₂)₃Si) 7.48(dd, J=8.1, 7.5 Hz, 2 H, benzoate, m), 7.61(tt,J=7.5, 1.3 Hz, 1 H, benzoate, p), 8.10(d, J=8.1, 1.3 Hz, 2 H, benzoate,o) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 9.9(Me(19)), 15.0(Me(18)), 19.5(4-Ac),22.4, 26.7(Me16, Me17), 23.6(Si(CH₂Ph)3), 36.9(C(6)), 38.7(C(14)),42.7(C(15)), 46.8(C(3)), 58.0(C(8)), 68.0(C(13)), 74.4, 74.9, 75.0(C(7),C(2), C(10), C(20)), 78.8(C(1)), 80.8(C(4)), 84; 1(C(5)), 124.9, 128.7,128.8, 129.1, 129.8, 130.3, 133.8, 137.8(Si(CH₂Ph)₃, benzoate),135.5(C(11)), 142.2(C(12)), 167.4(benzoate), 170.9(4-Ac),210.8(C(9))ppm. Anal. Calcd for C₅₀H₅₆O₁₀Si. 1/2H₂O: C, 70.32; H, 6.73.Found: C, 70.11; H, 6.57.

EXAMPLE 4 Selective Acylation of 10-acyl-10-DAB

10-Alloc-7-p-Nitrobenzyloxycarbonyl-10-DAB. To a mixture of10-alloc-10-DAB (33 mg, 0.053 mmol) and DMAP (19.3 mg, 0.16 mmol, 3equiv) in dichloromethane (4 mL) at 0° C. was added a dichloromethanesolution (1 mL) of p-nitrobenzyl chloroformate (23 mL, 0.11 mmol, 2equiv) under N₂. The reaction mixture was stirred at 0° C. for 4 h.EtOAc (10 mL) was added, the solution was quickly filtered through ashort column of silica gel. The silica gel was washed with EtOAc (100mL), and the solution was concentrated under reduced pressure. Theresidue was purified by flash column chromatography using EtOAc: hexanes(1:2) as the eluent and dried overnight in vacuo to give10-alloc-7-p-nitrobenzyloxycarbonyl-10-DAB as a colorless solid: yield,34 mg (92%).

7-Benzyloxycarbonyl baccatin III. To a stirred solution of baccatin III(100 mg, 0.168 mmol) in methylene chloride under N₂ at room temperaturewas added 4-dimethylaminopyridine (204 mg, 1.68 mmol) followed byaddition of benzyl chloroformate (240 mL, 1.68 mmol). The reactionmixture was stirred at room temperature and the progress of the reactionwas monitored by TLC. After about 4 h the reaction was complete Themixture was diluted with EtOAc (10 mL) and was transferred to aseparatory funnel containing 50 mL of a 50% EtOAc/Hexanes. The mixturewas washed with saturated sodium bicarbonate and the organic layer wasseparated. The aqueous layer was washed with 20 mL of 50% EtOAc/Hexanes.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated under reduced pressure. The crude product was passedthrough a short column to give 115 mg (95%) of a white solid m.p.245-248° C.; [α]²⁵ _(D) −60.5° c (C-0.007, CHCl₃). ¹H NMR (CDCl₃, 400MHz) δ 8.10(d, J=9.6 Hz,2H, o-benzoate),7.60-6.8 (m, 8H, benzoate,Bn),6.45(s, 1H, H10), 5.63(d, J=6.9 Hz, 1H, H2b), 5.56 (dd, J=10.6, 7.2 Hz,1H H7), 5.56(dd, J=18.5, 12.0 Hz, 2H, Bn), 4.97(d, J=10.6, 1H, H5),4.87(m, 1H, H13), 4.31(d, J=10.5, 1H, H20a), 4.15 (d, J=10.5, 1H, H20b),4.02(d, J=6.9, 1H, H3), 2.61(m, 1H, H6a), 2.30(m, 2H, H14's), 2.29(s,3H, 4Ac), 2.18(s, 3H, 10Ac), 2.15(br s, 3H, Me18), 2.08(d, J=5.2 Hz,130H), 1.94(m, 1H, 6b), 1.79(s, 3H, Me19), 1.58(s, 1H, 1OH), 1.14(s, 3H,Me16), 1.09(s, 3H, Me17).

7-Allyloxycarbonyl baccatin III. To a stirred solution of baccatin III(30 mg, 0.051 mmol) in methylene chloride (1 mL) under N₂ at roomtemperature, was added 4-dimethylaminopyridine (62.3 mg, 0.51 mmol)followed by addition of allyl chloroformate (54 mL, 0.51 mmol).Thereaction mixture was stirred at room temperature and the progress of thereaction was followed by TLC. After about 1.5 h the reaction wascomplete The mixture was diluted by EtOAc (5 mL) and was transferred toa separatory funnel containing 50 mL of a 50% EtOAc/Hexanes. The mixturewas washed with saturated sodium bicarbonate and the organic layer wasseparated. The aqueous layer was washed with 10 mL of 50% EtOAc/Hexanes,the combined organic layers were washed with brine, dried over MgSO₄,and concentrated under reduced pressure. The crude product was passedthrough a short column to give 33.1 mg (97%) of a white solid m.p.239-244° C.; [α]²⁵ _(D) −61.5 c (0.01, CHCl₃) 1H NMR (CDCl₃, 500 MHz) δ8.12(d, J=8.3 Hz, 2H, o-benzoate), 7.66-7.45 (m, 3H, benzoate), 6.43(s,1H, H10), 5.97(m, 1H, int. allyl), 5.64(d, J=7.0 Hz, 1H, H2b), 5.54 (dd,J=10.5, 7.0, Hz, 1H, H7), 5.28(m, 2H, ext. allyl), 4.97(d, J=9.6 Hz, 1H,H5), 4.87(m, 1H, H13), 4.67(m, 2H, CH2allyl), 4.31(d, J=8.5 Hz, 1H,H20a), 4.17(d, J=8.5, 1H, H20b), 4.02(d, J=7.0, 1H, H3), 2.64(m, 1H,H6a), 2.30(d, J=8.0 Hz, 2H, H14's), 2.29(s, 3H, 4Ac), 2.16(s, 3H, 10Ac),2.15(br s, 3H, Me18), 2.01(d, J=5 Hz, 13OH), 1.96(m, 1H, 6b), 1.81(s,3H, Me19), 1.58(s, 1H, 10H), 1.15(s, 3H, Me16), 1.02(s, 3H, Me17).

EXAMPLE 5 Selective Ketalization of 10-acyl-10-DAB

7-MOP baccatin III. To a solution of baccatin III (101 mg, 0.172 mmol)in THF (8 mL) at −20° C. was added 2-methoxypropene (0.66 mL, 6.89 mmol,40 equiv), followed by the addition of a catalytic amount oftoluenesulfonic acid (0.1 M solution in THF, 43 μL, 0.004 mmol, 0.025equiv) under N₂. The reaction mixture was stirred at −20 ° C. for 3 h.TLC analysis indicated complete consumption of the starting material andthe formation of desired product as the only major product.Triethylamine (0.5 mL) was added, and the solution was warmed to roomtemperature, diluted with EtOAc (100 mL), washed with saturated aqueousNaHCO₃ solution, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was dried in vacuo overnight to give 112 mg (99%)of crude product. Recrystallization of the crude product fromEtOAc/hexanes gave 105 mg (93%) of 7-MOP baccatin III as a whitecrystal, mp 181-183° C.; ¹H NMR (500 MHz, C₆D₆) δ 1.01 (s, 3 H, Me17),1.11(br s, 1 H, 13-OH), 1.28(s, 3 H, Me16), 1.39, 1.78(2 s, 6 H, Me₂CO),1.62(s, 1 H, 1-OH) 1.78(s, 3 H, 10-Ac), 1.92(s, 3 H, 4-Ac), 2.09(s, 3 H,Me18), 2.12(s, 3 H, Me19), 2.14(ddd, J=15.0, 10.9, 2.2 Hz, 1 H, H6b),2.18(dd, J=15.6, 9.4 Hz, 1 H, H14b), 2.31(dd, J=15.6, 7.0 Hz, 1 H,H14b), 2.97(s, 3 H, MeO), 3.15(ddd, J=15.0, 9.9, 6.7 Hz, 1 H, H6a),4.08(d, J=7.0 Hz, 1 H, H3), 4.24(m, 1 H, H13), 4.33(d, J=8.3 Hz, 1 H,H20b), 4.41(d, J=8.3 Hz, 1 H, H20a), 4.78(dd, J=10.9, 6.7 Hz, 1 H, H7),4.97(dd, J=9.9, 2.2 Hz, 1 H, H5), 5.95(d, J=7.0 Hz, 1 H, H2), 6.79(s, 1H, H10), 7.15(m, 3 H, benzoate, m, p), 8.28(d, J=8.0 Hz, 2 H, benzoate,o) ppm; Anal. Calcd for C₃₅H₄₆O₁₂: C, 63.82; H, 7.04. Found: C, 63.72;H, 7.07.

EXAMPLE 6 Selective Acylation of 10-silyl-10-DAB

7-Acetyl-10-TES-10-DAB. To a stirred solution of 10-TES-10-DAB (65 mg,0.098 mmol) in dichloromethane (4 ml) at 0° C. under N₂, was added DMAP(36 mg, 0.296 mmol, 3 equiv), followed by addition of acetic anhydride(14 mL, 0.148 mmol, 1.5 equiv). The reaction mixture was stirred at 0°C. for 4.5 hrs and the TLC analysis indicated the complete consumptionof starting material. The reaction mixture was then filtered through ashort pad of silica gel, the silica gel was washed with EtOAc (100 mL)and the solutionwas concentrated under reduced pressure. The residue waspurified by flash chromatography using EtOAc:hexanes (1:2) as the eluentand dried in vaccuo overnight to give the 7-acetyl-10-TES-10-DAB: yield,65.7 mg (95%). ¹H NMR (CDCl₃, 400 MHz), δ 0.60(m, 6 H, (CH₃CH₂)₃Si),0.97(t, J=7.9 Hz, 9 H, (CH3CH₂)₃Si), 1.05(s, 3 H, Me17), 1.18(s, 3 H,Me16), 1.56(s, 1 H, 1-OH), 1.79(s, 3 H, Me19), 1.83(ddd, J=14.5, 10.3,2.0 Hz, 1 H, H6b), 1.97(m, 1 H, 13-OH), 2.00(s, 3 h, 7-Ac), 2.07(d,J=1.3 Hz, 3 H, Me18), 2.26(m, 2 H, H14a, H14b), 2.29(s, 3 H, 4-Ac),2.57(ddd, J=14.5, 9.5, 7.3 Hz, 1 H, H6a), 4.06(d, J=7.0 Hz, 1 H, H3),4.17(d, J=8.2 Hz, 1 H, H20b), 4.31(d, J=8.2 Hz, 1 H, H20a), 4.84(m, 1 H,H13), 4.94(dd, J=9.5, 2.0 Hz, 1 H, H5), 5.29(s, 1 H, H10), 5.46(dd,J=10.3, 7.3 Hz, 1 H, H7), 5.65(d, J=7.0 Hz, 1 H, H2), 7.47(m, 2 H,benzoate, m), 7.60(m, 1 H, benzoate, p), 8.11(d, J=8.0 Hz, 2 H,benzoate, o) ppm.

7-Troc-10-TES-10-DAB. To a mixture of 10-TES-10-DAB (40 mg, 0.061 mmol)and DMAP (72 mg, 0.61 mmol, 10 equiv) in dichloromethane (2 mL) wasadded trichloroethyl chloroformate (24 mL, 0.184 mmol, 3 equiv) underN₂. The reaction mixture was stirred at room temperature and theprogress of the reaction was monitored by TLC analysis. After 0.5 h, TLCanalysis indicated almost complete disapperance of 10-TES-10-DAB and theformation of the product as the only major spot. Methanol (5 mL) wasadded, and the solution was quickly filtered through a short column ofsilica gel. The silica gel was washed with EtOAc (100 mL), and thesolution was concentrated under reduced pressure. The residue waspurified by flash chromatography using EtOAc: CH₂Cl₂ (1:10) as theeluent and dried in vacuo overnight to give 7-Troc-10-TES-10-DAB as awhite solid: yield, 49 mg (97%); ¹H NMR (500 MHz, CDCl₃) δ 0.61 (m, 6 H,(CH₃CH₂)₃Si) 0.99(t, J=7.9, 9 H, (CH₃CH₂)₃Si), 1.08(s, 3 H, Me17),1.20(s, 3 H, Me16), 1.56(s, 1 H, 1-OH), 1.84(s, 3 H, Me19), 1.96(d,J=4.9 Hz, 1 H, 13-OH), 2.01(ddd, J=14.4, 10.5, 2.0 Hz, 1 H, H6b),2.08(d, J=1.2, 3 H, Me18), 2.29(m, 2 H, H14a, H14b), 2.29(s, 3 H, 4-Ac),2.68(ddd, J=14.4, 9.5, 7.3 Hz, 1 H, H6a), 4.08(d, J=6.7 Hz, 1 H, H3),4.18(d, J=8.5 Hz, 1 H, H20b), 4.32(d, J=8.5 Hz, 1 H, H20a), 4.43(d,J=11.9 Hz, 1 H, CHH′OC(O)), 4.86(m, 1 H, H13), 4.95(dd, J=9.3, 2.0 Hz, 1H, H5), 4.98(d, J=11.9 Hz, 1 H, CHH′OC(O)), 5.33(s, 1 H, H10), 5.37(dd,J=10.5, 7.3 Hz, 1 H, H7), 5.67(d, J=6.7 Hz, 1 H, H2), 7.48(dd, J=7.9,7.3 Hz, 2 H, benzoate, m), 7.60(tt, J=7.3, 1.2 Hz, 1 H, benzoate, p),8.11(dd, J=7.9, 1.2 Hz, 2 H, benzoate, o)ppm.

7-p-Nitrobenzyloxycarbonyl-10-TES-10-DAB. To a mixture of 10-TES-10-DAB(40 mg, 0.061 mmol) and DMAP (72 mg, 0.61 mmol, 10 equiv) in drychlorform (2 mL) was added p-nitrobenzyl chloroformate (131 mg, 0.61mmol, 10 equiv) under N₂. The reaction mixture was stirred at roomtemperature and the progress of the reaction was monitored by TLCanalysis. After 45 min, TLC analysis indicated almost completedisapperance of 10-TES-10-DAB and the formation of the product as theonly major spot. Methanol (10 mL) was added, and the solution wasquickly filtered through a short column of silica gel. The silica gelwas washed with EtOAc (100 mL), and the solution was concentrated underreduced pressure. The residue was purified by flash chromatography usingEtOAc: CH₂C₂ (1:10) as the eluent and dried in vacuo overnight to give7-p-Nitrobenzyloxycarbonyl-10-TES-10-DAB as a white solid: yield, 48.3mg (95%); ¹H NMR (500 MHz, CDCl₃) δ 0.60(m, 6 H, (CH₃CH₂)₃Si), 0.95(t,J=7.9, 9 H, (CH₃CH₂)₃Si), 1.08 (s, 3 H, Me17), 1.19 (s, 3 H, Me16)1.55(s, 1 H, 1-OH), 1.83(s, 3 H, Me19), 1.93(ddd, J=14.3, 10.4, 2.2 Hz,1 H, H6b), 1.96(d, J=4.9 Hz, 1 H, 13-OH), 2.09(d, J=1.2, 3 H, Me18),2.29(m, 2 H, H14a, H14b), 2.29(s, 3 H, 4-Ac), 2.65(ddd, J=14.3, 9.3, 7.3Hz, 1 H, H6a), 4.08(d, J=7.0 Hz, 1 H; H3), 4.18(d, J=8.6 Hz, 1 H, H20b),4.31(d, J=8.6 Hz, 1 H, H20a), 4.86(m, 1 H, H13), 4.95(dd, J=9.3, 2.2 Hz,1 H, H5), 5.06(d, J=13.4 Hz, 1 H, CHH′OC(O)), 5.31(d, J=13.4 Hz, 1 H,CHH′OC(O)), 5.33(s, 1 H, H10), 5.36(dd, J=10.4, 7.3 Hz, 1 H, H7),5.66(d, J=7.0 Hz, 1 H, H2), 7.48(dd, J=7.4, 7.3 Hz, 2 H, benzoate, m),7.53(d, J=8.9 Hz, 2 H, NO₂C₆H₄), 7.59(tt, J=7.3, 1.2 Hz, 1 H, benzoate,p), 8.12(dd, J=7.4, 1.2 Hz, 2 H, benzoate, o), 8.23(d, J=8.9 Hz, 2 H,NO₂C₆H₄) ppm.

7-Cbz-10-TES-10-DAB. To a mixture of 10-TES-10-DAB (40 mg, 0.061 mmol)and DMAP (440 mg, 3.64 mmol, 60 8 equiv) in dry chloroform (2 mL) wasslowly added four equal aliquot of benzyl chloroformate (4×130 mL, 3.64mmol, 60 equiv) via a syring in a 10-min interval under N₂ during aperiod of 40 min. The reaction mixture was then stirred at roomtemperature and the progress of the reaction was monitored by TLCanalysis. After 2 h, TLC analysis indicated almost complete disapperanceof 10-TES-10-DAB and the formation of the product as the only majorspot. Methanol (10 mL) was added, and the solution was poured into ethylacetate (100 mL), washed with a saturated aqueous NaHCO₃ solution, H₂O,and brine. The solution was dried over Na₂SO₄, concentrated underreduced pressure. The residue was purified by flash chromatography usingEtOAc: CH₂Cl₂ (1:10) as the eluent and dried in vacuo overnight to give7-CBz-10-TES-10-DAB as a white solid: yield, 45 mg (93%); ¹H NMR (500MHz, CDCl₃) δ 0.62(m, 6 H, (CH₃CH₂)₃Si), 0.97(t, J=7.9, 9 H,(CH₃CH₂)₃Si), 1.07 (s, 3 H, Me17), 1.20 (s, 3 H, Me16) 1.55(s, 1 H,1-OH), 1.81(s, 3 H, Me19), 1.91(ddd, J=14.3, 10.5, 2.1 Hz, 1 H, H6b),1.96(d, J=4.9 Hz, 1 H, 13-OH), 2.10(d, J=1.2, 3 H, Me18), 2.28(m, 2 H,H14a, H14b), 2.28(s, 3 H, 4-Ac), 2.64(ddd, J=14.3, 9.5, 7.3 Hz, 1 H,H6a), 4.08(d, J=7.0 Hz, 1 H, H3), 4.17(d, J=8.5 Hz, 1 H, H20b), 4.30(d,J=8.5 Hz, 1 H, H20a), 4.86(m, 1 H, H13), 4.95(dd, J=9.5, 2.1 Hz, 1 H,H5), 5.01(d, J=12.2 Hz, 1 H, CHH′OC(O)), 5.24(d, J=12.2 Hz, 1 H,CHH′OC(O)), 5.34(s, 1 H, H10), 5.37(dd, J=10.5, 7.3 Hz, 1 H, H7),5.65(d, J=7.0 Hz, 1 H, H2), 7.32-7.37(m, 5 H, PhCH₂O), 7.47(dd, J=8.3,7.3 Hz, 2 H, benzoate, m), 7.59(tt, J=7.3, 1.3 Hz, 1 H, benzoate, p),8.12(dd, J=8.3, 1.3 Hz, 2 H, benzoate, o) ppm.

EXAMPLE 7 Selective Silylation of 10-acyl-10-DAB

7-dimethylisopropylsilyl baccatin III. To a stirred solution of baccatinIII (30 mg, 0.051 mmol) in pyridine (0.6 mL) at 0° C. under N₂, wasadded chlorodimethyl-isopropylsilane (160 uL, 1.02 mmol). The reactionmixture was stirred at that temperature and the progress of the reactionwas monitored by TLC. After about 1.5 h the reaction was complete. Ethylacetate (5 mL) was added and the solution was transferred to aseparatory funnel containing 50 mL of a 50% EtOAc/Hexanes. The mixturewas washed with saturated sodium bicarbonate and the organic layer wasseparated. The aqueous layer was extracted with 10 mL of 50%EtOAc/Hexanes and the combined organic layers were washed with saturatedsodium chloride, dried over MgSO₄, concentrated under reduced pressure.The crude product was passed through a short silica gel column to give33.9 mg (97%) of a white solid m.p. 204-207° C; [α]²⁵ _(D) −58.6° c(0.009, CHCl₃). ¹HNMR (CDCl₃, 500 MHz), δ 8.10(d, J=8.4 Hz, 2H,o-benzoate), 7.60-7.20 (m, 3H, benzoate), 6.4 (s, 1H, H10), 5.64(d,J=7.1 Hz, 1H, H2b), 4.95(d, J=4.9 Hz, 1H, H5), 4.84(m, 1H, H13),4.44(dd, J=10.4, 6.8 Hz, 1H, H7), 4.30(d, J=8.3 Hz, 1H, H20a), 4.14 (d,J=8.3 Hz, 1H, H20b), 4.15(d, J=7.2 Hz, 1H, H3), 2.49(m, 1H, H6a),2.23(m, 2H, H14's), 2.28(s, 3H, 4Ac), 2.18(br s, 3H, Me 18), 2.17(s, 3H,10Ac), 2.01(d, J=5.0 Hz, 13 OH), 1.86(m, 1H, 6b), 1.69(s, 3H, Me19),1.61(s, 1H, 1OH), 1.20(s, 3H, Me16), 1.05(s, 3H, Me17), 0.87(d, J=7.1Hz, 6H, i-pr), 0.73(m, 1H, i-pr), 0.09(s, 6H, Me2Si).

7-dimethylphenylsilyl baccatin III. To a stirred solution of baccatinIII (20 mg, 0.034 mmol) in THF (1.25 mL) at −10° C. under N₂, was addedchlorodimethyphenyl-silane (68 uL, 0.41 mmol), followed by addition ofpyridine (250 mL, 3.1 mmol). The reaction mixture was stirred at thattemperature and the progress of the reaction was monitored by TLC. Afterabout one hour the reaction was complete. Ethyl acetate (5 mL) was addedand the solution was transferred to a separatory funnel containing 30 mLof 50% EtOAc/Hexanes. The mixture was washed with saturated sodiumbicarbonate and the organic layer was separated. The aqueous layer wasextracted with 10 mL of 50% EtOAc/Hexanes and the combined organiclayers were washed with saturated sodium chloride, dried over MgSO₄,concentrated under reduced pressure. The crude product was passedthrough a short silica gel column to give 24.1 mg (98%) of a white solidm.p. 210-213° C.; [α]²⁵ _(D) −58.3.5° c (0.005, CHCl₃) ¹H NMR (CDCl₃,500 MHz) δ 8.35(d, J=8.5 Hz,2H, o-benzoate), 7.627.25(m, 8H, benzoate,phenyl), 6.42 (s, 1H, H10), 5.64 (d, J=6.9 Hz, 1H, H2b), 4.84(m, 1H,H5), 4.81(m, 1H, H13), 4.46 (dd, J=10.6, 6.9 Hz, 1H, H7), 4.21(d, J=8.5Hz, 1H, H20a), 4.14 (d, J=8.5 Hz, 1H, H20b), 3.85(d, J=6.9 Hz, 1H, H3),2.34(m, 1H, H6a), 2.26(d, J=8 Hz, 2H, H14's), 2.24(s, 3H, 4Ac), 2.15(s,3H, 10Ac), 2.02(br d, J=1 Hz, 3H, Me 18), 1.93(d, J=5 Hz, 1H, 13OH),1.77(m, 1H, 6b), 1.72(s, 3H, Me19), 1.59(s, 1H, 1H), 1.20(s, 3H, Me16),1.05(s, 3H, Me17), 0.446(s, 3H, Me Si), 0.335(s, 3H, Me Si).

7-dimethylphenylsilyl-10-propionyl-10-DAB. To a stirred solution of10-propionyl-10-DAB (0.200 g, 0.333 mmol) in THF (12 mL) at −10° C., wasadded chlorodimethyl-phenylsilane (0.668 mL, 4.00 mmol) followed bypyridine dropwise (2.48 mL, 30.64 mmol). The reaction was stirred for 90minutes. Ethyl acetate (20 mL) was added and the solution transferred toa separatory funnel containing 100 mL of 50% EtOAc/Hexanes. The mixturewas washed with saturated sodium bicarbonate and the organic layerseparated. The aqueous layer was extracted with 50% EtOAc/Hexanes (30mL) and the combined organic extracts washed with saturated sodiumchloride, dried over Na₂SO₄, concentrated in vacuo. The crude solid wasthen purified with flash column chromatography using 50% EtOAc/hexane aseluent to give 7-dimethylphenylsilyl-10-propionyl-10-DAB (0.242 g, 99%)as a solid. ¹H NMR (CDCl₃, 500 MHz), δ 0.34, 0.45(2 s, 6 H. Me₂Si), 1.05(s, 3 H, Me17), 1.20(t, J=7.5 Hz, 3 H, CH₃CH₂), 1.21(s, 3 H, Me16),1.60(s, 1 H, 1-OH), 1.72(s, 3 H, Me19), 1.78(ddd, J=14.5, 10.0, 2.0 Hz,1 H, H6b), 2.04(m, 1 H, 13-OH), 2.05(s, 3 H, Me18), 2.27(m, 2 H, H14a,H14b), 2.25(s, 3 H, 4-Ac), 2.34(ddd, J=14.5, 9.5, 7.0 Hz, 1 H, H6a),2.42, 2.49(2 dq, J=16.5, 7.5 Hz, 6 H, CH₃CH₂), 3.87 (d, J=7.5 Hz, 1 H,H3), 4.14 (d, J=8.0 Hz, 1 H, H20b), 4.27(d, J=8.0 Hz, 1 H, H20a),4.47(dd, J=10.0, 7.0 Hz, 1 H, H7), 4.82(m, 1 H, H13), 4.85(dd, J=9.5,2.0 Hz, 1 H, H5), 5.64(d, J=7.5 Hz, 1 H, H2), 6.44(s, 1 H, H10),7.32-7.36, 7.55-7.57(2 m, 5 H, PhSi), 7.46(m, 2 H, benzoate, m), 7.59(m,1 H, benzoate, p), 8.10(d, J=8.0 Hz, 2 H, benzoate, o) ppm.

7-Dimethylphenylsilyl-10-cyclopropanecarbonyl-10-DAB. To a solution of10-cyclopropanecarbonyl-10-DAB (680 mg, 1.1 mmol) in THF (25 mL) wereadded with stirring pyridine (3.5 mL) and thenchlorodimethyl-phenylsilane (1.8 mL, 11 mmol) at −10° C. under N₂. Thesolution was stirred till the reaction completed. Then quenched withsat. NaHCO₃ (20 mL). The mixture was extracted with EtOAc (2×250 mL).The combined organic layers were washed with brine (2×10 mL), dried andfiltered. Concentration of the filtrate in vacuo and followed by flashchromatography (hexane:EtOAc, 4:1) gave7-Dimethyl-phenylsilyl-10-cyclopropane-carbonyl-10-DAB (816 mg, ˜100%).¹H NMR (CDCl₃, 500 MHz), δ 0.32, 0.43(2 s, 6 H, Me₂Si), 0.91, 1.00,1.17(3 m, 5 H, cyclopropyl) 1.07(s, 3 H, Me17), 1.21(s, 3 H, Me16),1.73(s, 3 H, Me19), 1.74(s, 1 H, 1-OH), 1.78(ddd, J=14.4, 10.5, 2.1 Hz,1 H, H6b), 2.04(m, 1 H, 13-OH), 2.05(d, J=1.5 Hz, 3 H, Me18), 2.24(s, 3H, 4-Ac), 2.26(m, 2 H, H14a, H14b), 2.34(ddd, J=14.4, 9.5, 6.7 Hz, 1 H,H6a), 3.87(d, J=7.0 Hz, 1 H, H3), 4.15(d, J=8.2 Hz, 1 H, H20b), 4.26(d,J=8.2 Hz, 1 H, H20a), 4.46(dd, J=10.5, 6.7 Hz, 1 H, H7), 4.82(m, 1 H,H13), 4.85(dd, J=9.5, 2.1 Hz, 1 H, H5), 5.65(d, J=7.0 Hz, 1 H, H2),6.44(s, 1 H, H10), 7.32-7.36, 7.55-7.57(2 m, 5 H, PhSi), 7.46(m, 2 H,benzoate, m), 7.59(m, 1 H, benzoate, p), 8.10(d, J=8.0 Hz, 2 H,benzoate, o) ppm.

EXAMPLE 8

7-p-Nitrobenzyloxycarbonyl-10-DAB. To a THF solution (1 mL) of10-alloc-7-p-nitrobenzyloxycarbonyl-10-DAB (34 mg, 0.048 mmol) at roomtemperature was added a THF solution (1 mL) of formic acid (19 mL, 0.48mmol, 10 equiv) and butylamine (47 mL, 0.48 mmol, 10 equiv), followed bythe addition of Pd(PPh₃)₄ under N₂. The reaction mixture was stirred atroom temperature for 0.5 h. EtOAc (10 mL) was added, and the solutionwas quickly filtered through a short column of silica gel. The silicagel was washed with EtOAc (100 mL), and the solution was concentratedunder reduced pressure. The residue was purified by flash columnchromatography using EtOAc: hexanes (1:2) as the eluent and dried invacuo to give 7-p-nitrobenzyloxycarbonyl-10-DAB as a colorless solid:yield, 28 mg (93%). [α]_(Hg) −38° (CHCl₃, c=0.48); ¹H NMR (400 MHz,CDCl₃) δ 1.06(s, 3 H, Me16), 1.09(s, 3 H, Me17), 1.55(s, 1 H, 1-OH),1.86(s, 3 H, Me19), 2.01(ddd, J=14.4, 10.7, 2.0 Hz, 1 H, H6b), 2.03(d,J=5.1 Hz, 1 H, 13-OH), 2.09(d, J=1.3, 3 H, Me18), 2.28(m, 2 H, H14a,H14b), 2.30(s, 3 H, 4-Ac), 2.62(ddd, J=14.4, 9.5, 7.3 Hz, 1 H, H6a),3.89(d, J=2.0 Hz, 1 H, 10-OH), 4.08(d, J=6.9 Hz, 1 H, H3), 4.20(d, J=8.4Hz, 1 H, H20b), 4.34(d, J=8.4 Hz, 1 H, H20a), 4.88(m, 1 H, H13),4.96(dd, J=9.5, 2.0 Hz, 1 H, H5), 5.19(d, J=13.3, 1 H, CHH′OC(O)),5.26(d, J=13.3, 1 H, CHH′OC(O)), 5.36(dd, J=10.7, 7.3 Hz, 1 H, H7),5.40(d, J=2.0 Hz, 1 H, H10), 5.64(d, J=6.9 Hz, 1 H, H2), 7.48(dd, J=8.1,7.5 Hz, 2 H, benzoate, m), 7.52(d, J=8.7, 2 H, NO₂C₆H₄), 7.61 (tt,J=7.5, 1.3 Hz, 1 H, benzoate, p), 8.10(d, J=8.1, 1.3 Hz, 2 H, benzoate,o), 8.26(d, J=8.7, 2 H, NO₂C₆H₄) ppm. ¹³C NMR (75 MHz, CDCl₃) δ10.5(Me(19)), 14.6(Me(18)), 19.4(4-Ac), 22.2, 26.4(Me16, Me17),33.2(C(6)), 38.7(C(14)), 42.4(C(15)), 46.5(C(3)), 56.5(C(8)), 67.9,68.3(C(13), OCH₂Ph—NO₂-p), 74.7, 75.2, 76.8(C(7), C(2), C(10), C(20)),78.8(C(1)), 80.4(C(4)), 83.6(C(5)), 124.1, 128.4, 128.9, 130.3, 133.9(OCH₂Ph—NO₂-p, benzoate), 135.0(C(11)), 142.4, 143.0 (OCH₂Ph—NO₂-p,C(12)), 154.2 (OC(O)O), 167.3 (benzoate) 171.1(4-Ac), 211.6(C(9))ppm.

EXAMPLE 9

Selective Esterification of the C-10 Hydroxyl of 10-DAB using thecatalytic DyCl₃ reaction: A solution of butyric anhydride (0.55 mmol) inTHF (1.32 ml) was added, under a nitrogen atmosphere, to a solid mixtureof 10-DAB (30 mg, 0.055 mmol) and DyCl₃ (1.3 mg, 10 mol. % wrt 10-DAB).The resulting suspension was stirred at room temperature until judgedcomplete by TLC (2:1 EtOAc/Hexane). The reaction was diluted with EtOAcand washed three times with saturated NaHCO₃ solution. The combinedbicarbonate washings were extracted three times with EtOAc, thesecombined organics were dried (Na₂SO₄) and the solvent evaporated. Thecrude product was triturated with hexanes and the mother liquorsdecanted away. Crystallization from EtOAc/hexanes yielded10-butyrl-10-DAB identical to that isolated from the CeCl₃ catalysedreaction.

EXAMPLE 10

Selective Esterification of the C-10 Hydroxyl of 10-DAB using thecatalytic YbCl₃ reaction: A solution of butyric anhydride (0.55 mmol) inTHF (1.32 ml) was added, under a nitrogen atmosphere, to a solid mixtureof 10-DAB (30 mg, 0.055 mmol) and YbCl₃ (1.3 mg, 10 mol.% wrt 10-DAB).The resulting suspension was stirred at room temperature until judgedcomplete by TLC (2:1 EtOAc/Hexane). The reaction was diluted with EtOAcand washed three times with saturated NaHCO₃ solution. The combinedbicarbonate washings were extracted three times with EtOAc, thesecombined organics were dried (Na₂SO₄) and the solvent evaporated. Thecrude product was triturated with hexanes and the mother liquorsdecanted away. Crystallization from EtOAc/hexanes yielded10-butyrl-10-DAB identical to that isolated from the CeCl₃ catalysedreaction.

In view of the above, it will be seen that the several objects of theinvention are achieved.

As various changes could be made in the above compositions withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description be interpreted as illustrativeand not in a limiting sense.

1. A taxane having the structure

wherein M is a metal or comprises ammonium: R₁ is hydrogen, hydroxy,protected hydroxy, or together with R₁₄ or R₂ forms a carbonate; R₂ isketo, —OT₂, acyloxy, or together with R₁ forms a carbonate; R₄ is —OT₄or acyloxy; R₇ is —OSi(Me)₂Ph; R₉ is hydrogen, keto, —OT₉, or acyloxy;R₁₀ is hydrogen, keto, —OT₁₀, or acyloxy; R₁₃ is hydroxy, protectedhydroxy, keto, or MO—; R₁₄ is hydrogen, —OT₁₄, acyloxy, or together withR₁ forms a carbonate; and T₂, T₄, T₉, T₁₀, and T₁₄ are independentlyhydrogen or hydroxy protecting group.
 2. A taxane having the structure

wherein R₁ is hydroxy or together with R₁₄ or R₂ forms a carbonate; R₂is —OCOZ₂, —OCOOZ₂, or together with R₁ forms a carbonate; R₄ is —OCOZ₄;R₇ is —OSi(Me)₂Ph; R₉ is hydrogen or keto; R₁₀ is hydrogen, keto,hydroxy, protected hydroxy, or acyloxy; R₁₃ is hydroxy, protectedhydroxy, or

R₁₄ is hydrogen, hydroxy, protected hydroxy, or together with R₁ forms acarbonate; X₁ is —OX₆ or —NX₈X₉; X₂ is hydrogen, hydrocarbyl, orsubstituted hydrocarbyl; X₃ and X₄ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, or heteroaryl; X₅ is —X₁₀, —OX₁₀,or —NX₈X₁₀; X₆ is a hydroxy protecting group; X₈ is hydrogen,hydrocarbyl, or substituted hydrocarbyl; X₉ is an amino protectinggroup; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heteroaryl; andZ₂ and Z₄ are independently hydrocarbyl, substituted hydrocarbyl, orheteroaryl.
 3. The taxane of claim 1 wherein R₁₀ is hydroxy, protectedhydroxy or acyloxy.
 4. The taxane of claim 2 wherein R₁₀ is hydroxy,protected hydroxy or acyloxy.
 5. The taxane of claim 1 having thestructure


6. The taxane of claim 1 having the structure


7. The taxane of claim 1 having the structure


8. The taxane of claim 1 having the structure


9. The taxane of claim 1 having the structure


10. The taxane of claim 2 having the structure


11. The taxane of claim 2 having the structure


12. A process for preparing a C(7) dimethylphenylsilyloxy substitutedtaxane, the process comprising treating a C(7) hydroxy substitutedtaxane with a dimethylphenylsilyl halide in the presence of a pyridine,the C(7) dimethylphenylsilyloxy substituted taxane having the structure

and the C(7) hydroxy substituted taxane having the structure

wherein R₁₀ is acyloxy, trialkylsilyloxy or hydroxy.
 13. The process ofclaim 12 wherein R₁₀ is acetoxy.
 14. The process of claim 12 wherein R₁₀is propionyloxy.
 15. The process of claim 12 wherein R₁₀ iscyclopropylcarbonyloxy.
 16. The process of claim 12 wherein R₁₀ ishydroxy.
 17. The process of claim 12 wherein R₁₀ is dimethylt-butylsilyloxy.
 18. The process of claim 12 wherein R₁₀ istrimethylsilyloxy.
 19. The process of claim 12 wherein R₁₀ istriethylsilyloxy.